USPTO Patents Application 09993647

WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau

PCT

INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) International Patent Classification ^
A61K 31/17

Al

(11) International Publication Number: WO 97/29743

(43) International Publication Date: 21 August 1997 (21.08.97)

(21) International Application Number: PCT/US96/13632

(22) International Filing Date: 21 August 1996 (21.08.96)

(30) Priority Data:

PCT/US96/02260 16 February 1996 (16.02.96) WO
(34) Countries for which the regional or

international application was filed: US et al.

(60) Parent Application or Grant

(63) Related by Continuation
US

Filed on

PCT/US96/02260 (CIP)
16 February 1996 (16.02.96)

(71) Applicant (for all designated States except US): SMITHKLINE

BEECH AM CORPORATION [US/US]; Corporate Intellec-
tual Property, UW2220, 709 Swedeland Road, P.O. Box
1539, King of Prussia, PA 19406-0939 (US).

(72) Inventors; and

(75) Inventors/Applicants (for US only): WIDDOWSON, KatheT-
ine, Louisa [CA/US]; 1047 Old Valley Forge Road, King of
Prussia, PA 19406 (US). VEBER, Daniel, Frank [US/US];
290 Batlcson Road, Ambler, PA 19002 (US). JUREWICZ,
Anthony, Joseph [US/US]; 523 Fruit Farm Road, Royers-

ford, PA 19468 (US). RUTLEDGE, Melvin, Clarence, Jr.
[US/US]; 2148 Schultz Road, Lansdale, PA 19446 (US).
HERTZBERG, Robert, Philip [US/US]; 121 Longfields
Way, Downingtown, PA 19335 (US).

(74) Agents: DINNER, Dara, L. et al.; SmithKline Beecham
Corporation, Corporate Intellectual Property, UW2220, 709
Swedeland Road, P.O. Box 1539, King of Prussia, PA
19406-0939 (US).

(81) Designated States: AL, AM, AU, BB, BG, BR, CA, CN, CZ,
EE, GE, HU, IL, IS, JP, KG, KP, KR, LK, LR, LT, LV,
MD, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK,
TR, TT, UA, US, UZ, VN, ARIPO patent (KE, LS, MW,
SD, SZ, UG), Eurasian patent (AM, AZ, BY, KG, KZ, MD,
RU, TJ, TM), European patent (AT, BE, CH. DE, DK, ES,
FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OAPI patent
(BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD,
TG).

Published

With international search report.

(54) Title: IL-8 RECEPTOR ANTAGONISTS
(57) Abstract

This invention relates to novel compounds and a novel use of phenyl ureas in the treatment of disease states mediated by the
chemokine, Interleukin-8 (IL-8).

FOR THE PURPOSES OF INFORMATION ONLY

Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
applications under the PCT.

AM

Armenia

AT

Austria

AU

Australia

BB

Barbados

BE

Belgium

BF

Burkina Faso

BG

Bulgaria

BJ

Benin

BR

Brazil

BY

Belarus

CA

Canada

CF

Central African Republic

CG

Congo

CH

Switzerland

CI

Cote d'lvoire

CM

Cameroon

CN

China

CS

Czechoslovakia

CZ

Czech Republic

DE

Germany

DK

Denmark

EE

Estonia

ES

Spain

FI

Finland

FR

France

GA

Gabon

GB

United Kingdom

MW

GE

Georgia

MX

GN

Guinea

NE

GR

Greece

NL

HU

Hungary

NO

IE

Ireland

NZ

IT

Italy

PL

JP

Japan

IT

KE

Kenya

RO

KG

Kyrgystan

RU

KP

Democratic People's Republic

SD

of Korea

SE

KR

Republic of Korea

SG

KZ

Kazakhstan

SI

LI

Liechtenstein

SK

L.K

Sri Lanka

SN

L.R

Liberia

SZ

LT

Lithuania

TD

LU

Luxembourg

TG

LV

Latvia

TJ

MC

Monaco

TT

MD

Republic of Moldova

UA

MG

Madagascar

UG

ML

Mali

US

MN

Mongolia

uz

MR

Mauritania

VN

Malawi
Mexico
Niger

Netherlands

Norway

New Zealand

Poland

Portugal

Romania

Russian Federation

Sudan

Sweden

Singapore

Slovenia

Slovakia

Senegal

Swaziland

Chad

Togo

Tajikistan

Trinidad and Tobago

Ukraine

Uganda

United States of America

Uzbekistan

Viet Nam

WO 97/29743

PCT/US96/13632

IL-8 RECEPTOR ANTAGONISTS

5

FIELD OF THE INVENTION

This invention relates to a novel group of phenyl urea compounds, processes for
the preparation thereof, the use thereof in treating IL-8, GROot, GROp\ GROy and
NAP-2 mediated diseases and pharmaceutical compositions for use in such therapy.

10

BACKGROUND OF THE INVENTION

Many different names have been applied to Interleukin-8 (IL-8), such as
neutrophil attractant/activation protein- 1 (NAP-1), monocyte derived neutrophil
chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell

15 lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils,
basophils, and a subset of T-cells. It is produced by a majority of nucleated cells
including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF,
IL-la, IL-lb or LPS, and by neutrophils themselves when exposed to LPS or
chemotactic factors such as FMLP. M. Baggiolini et al, J. Clin. Invest. 84, 1045

20 (1989); J. Schroder et al, J. Immunol. 739, 3474 (1987) and J. Immunol. 144 . 2223

(1990) ; Stricter, et al, Science 243 . 1467 (1989) and J. Biol. Chem. 264 . 10621 (1989);
Cassatella et al, J. Immunol. 148 . 3216 (1992).

GROa, GROp\ GROy and NAP-2 also belong to the chemokine a family. Like
IL-8 these chemokines have also been referred to by different names. For instance

25 GROoc, {5, y have been referred to as MGSAa, b and g respectively (Melanoma Growth
Stimulating Activity), see Richmond et al, J. Cell Physiology 129, 375 (1986) and
Chang et al, J. Immunol 148, 451 (1992). All of the chemokines of the a-family which
possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.
IL-8, GROa, GROp\ GROy and NAP-2 stimulate a number of functions in

30 vitro. They have all been shown to have chemoattractant properties for neutrophils,
while EL-8 and GROa have demonstrated T- lymphocytes, and basophiles chemotactic
activity. In addition IL-8 can induce histamine release from basophils from both
normal and atopic individuals GRO-a and IL-8 can in addition, induce lysozomal
enzyme release and respiratory burst from neutrophils. EL-8 has also been shown to

35 increase the surface expression of Mac-1 (CD1 lb/CD18) on neutrophils without de

novo protein synthesis. This may contribute to increased adhesion of the neutrophils to
vascular endothelial cells. Many known diseases are characterized by massive

WO 97/29743

PCT/US96/13632

neutrophil infiltration. As IL-8, GROa, GROP, GROy and NAP-2 promote the
accumulation and activation of neutrophils, these chemokines have been implicated in a
wide range of acute and chronic inflammatory disorders including psoriasis and
rheumatoid arthritis, Baggiolini et al, FEBS Lett. 307 . 97 (1992); Miller et al, Crit. Rev.
5 Immunol. 12 . 17 (19921: Qppenheimet al, Annu. Rev. Immunol. 9 . 617 f 199 1); Seitz
et al., J. Clin. Invest. 87 . 463 (1991); Miller et al.. Am. Rev. Respir. Pis. 146 . 427
(1992); Donnely et al., Lancet 341 . 643 (1993). In addition the ELR chemokines
(those containing the amino acids ELR motif just prior to the CXC motif) have also
been implicated in angiostasis. Strieter et al, Science 258, 1798 (1992).
10 In vitro, IL-8, GROa, GROfJ, GROy and NAP-2 induce neutrophil shape

change, chemotaxis, granule release, and respiratory burst, by binding to and activating
receptors of the seven-transmembrane, G-protein-linked family, in particular by binding
to IL-8 receptors, most notably the B-receptor. Thomas et al., J. Biol. Chem. 266 .
14839 (1991); and Holmes et al.. Science 253 . 1278 (1991). The development of non-
15 peptide small molecule antagonists for members of this receptor family has precedent.
For a review see R. Freidinger in: Progress in Drug Research . Vol. 40, pp. 33-98,
Birkhauser Verlag, Basel 1993. Hence, the DL-8 receptor represents a promising target
for the development of novel anti-inflammatory agents.

Two high affinity human IL-8 receptors (77% homology) have been
20 characterized: IL-8Ra, which binds only IL-8 with high affinity, and IL-8Rb, which has
high affinity for IL-8 as well as for GRO-a, GROb, GROg and NAP-2. See Holmes et
al.. supra; Murphy et al., Science 253 . 1280 (1991); Lee et al., J. Biol. Chem. 267,
16283 (1992); LaRosa et al., J. Biol. Chem. 267 . 25402 (1992); and Gayle et al., L
Biol. Chem. 268 . 7283 (1993).
25 There remains a need for treatment, in this field, for compounds which are

capable of binding to the IL-8 a or b receptor. Therefore, conditions associated with an
increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-
cells subsets into the inflammatory site) would benefit by compounds which are
inhibitors of IL-8 receptor binding.

30

SUMMARY OF THE INVENTION

This invention provides for a method of treating a chemokine mediated disease,
wherein the chemokine is one which binds to an IL-8 a or b receptor and which method
comprises administering an effective amount of a compound of Formula (I) or a
35 pharmaceutical^ acceptable salt thereof. In particular the chemokine is TL-8.

WO 97/29743 PCTVUS96/ 1 3632

This invention also relates to a method of inhibiting the binding of IL-8 to its
receptors in a mammal in need thereof which comprises administering to said mammal
an effective amount of a compound of Formula (I).

Compounds of Formula (I) useful in the present invention are represented by the
5 structure:

wherein

X is oxygen or sulfur;

10 R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
Cuioalkoxy; azide; S(0) t R4; (CRgRg)q S(0) t R4; hydroxy; hydroxy substituted
Ci-4alkyl; aryl; aryl C{-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci-4 alkyloxy;

15 heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;

heterocyclic, heterocyclic Ci-4aJkyl; heterocyclicCi_4alkyloxy; heterocyclicC2-10
alkenyl; (CR 8 R 8 )q NR4R5; (CR 8 R 8 )q C(0)NR4R5; C2-10 alkenyl C(0)NR4R5;
(CR 8 Rg)q C{O)NR4Rl0; S(0)3H; S(0)3R8; (CRgRg)q C(0)Rll; C2-10 alkenyl
C(0)Rn; C2-10 alkenyl C(0)ORn; (CR 8 R 8 )q C(0)ORn; (CR 8 R 8 )q OC(0)Rn ;

20 (CR 8 R 8 )qNR4C(0)R 1 1 ; (CRgRg)q C(NR4)NR 4 R 5 ; (CR 8 Rg)q NR4C(NR 5 )R n ,'

(CR 8 R 8 )q NHS(0) 2 Ri3; (CR 8 R 8 )q S(0) 2 NR4R5, or two Ri moieties together may
form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;

25 s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic
C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form

30 a 5 to 7 member ring which may optionally comprise an additional heteroatom

selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2- 10
alkenyl; Ci-io alkoxy; halosubstituted Ci- 10 alkoxy; azide; (CR 8 R 8 )qS(0) t R4,
(CRgR 8 )qOR4; hydroxy; hydroxy substituted Chalky 1; aryl; aryl Ci-4 alkyl;

- 3 -

WO 97/29743

PCT/US96/13632

aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl Ci-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CRgR^qNR^s; C2-10 alkenyl
C(0)NR4R5; (CRgR 8 )qC(0)NR4R5; (CRgRg)q C(O)NR4Rl0; S(0)3R8;

5 (CR 8 R 8 )qC(0)Rn; C2-10 alkenylC(0)Ri 1; (CR 8 R 8 )qC(0)ORn ;

C2-10alkenylC(O)ORn; (CR 8 R 8 )qOC(0)Ri 1; (CR 8 R 8 )qNR4C(0)Ri 1;
(CR 8 R 8 )qNHS(0) 2 Rb; (CR 8 R 8 )qS(0) 2 NR 4 R 5 ; (CR 8 R 8 )qC(NR 4 )NR 4 R 5 ;
(CRgR 8 )q NR 4 C(NR5)Ri 1; or two Y moieties together may form 0-(CH2)sO- or a
5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,

10 heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally

substituted;

q is 0 or an integer having a value of 1 to 10;
m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together
15 with the nitrogen to which they are attached form a 5 to 7 member ring which ring

may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;
R 8 is hydrogen or Ci- 4 alkyl;

RlO is Ci-10 alkyl C(0) 2 R 8;
20 Rl 1 is hydrogen, optionally substituted Ci- 4 alkyl, optionally substituted aryl,

optionally substituted aryl Ci- 4 alkyl, optionally substituted heteroaryl, optionally
substituted heteroarylCi- 4 alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC i- 4 alkyl;
Rl2 is hydrogen, Ci-10 alkyl, optionally substituted aryl or optionally substituted

25 arylalkyl;

Rl3 is suitably Cl- 4 alkyl, aryl, aryl Ci- 4 alkyl, heteroaryl, heteroarylCi- 4 alkyl,

heterocyclic, or heterocyclicC i- 4 alkyl;
R b is NR6R7, alkyl, aryl, aryl alkyl, aryl C 2 . 4 alkenyl, heteroaryl, heteroaryl

C 1^ alkyl, heteroarylC 2 - 4 alkenyl, heterocyclic, heterocyclic C i_ 4 alkyl,
30 heterocyclic C2- 4 alkenyl, or camphor, all of which groups may be optionally

substituted;

or a pharmaceutically acceptably salt thereof.

Another aspect of the present invention is to a method of treating a chemokine
35 mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor
and which method comprises administering an effective amount of a compound of
Formula (II) or a pharmaceutically acceptable salt thereof, as defined herein.

-4-

WO 97/29743 PCT/US96/13632

This invention also relates to a method of inhibiting the binding of IL-8 to its
receptors in a mammal in need thereof which comprises administering to said mammal
an effective amount of a compound of Formula (II), as defined herein.

This invention also relates to the novel compounds of Formula (II), or a
5 pharmaceutically acceptable salt thereof, as defined herein.

Another aspect of the present invention is to a method of treating a chemokine
mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor
and which method comprises administering an effective amount of a compound of
Formula (III) or a pharmaceutically acceptable salt thereof, as defined herein.
10 This invention also relates to a method of inhibiting the binding of IL-8 to its

receptors in a mammal in need thereof which comprises administering to said mammal
an effective amount of a compound of Formula (III), as defined herein.

This invention also relates to the novel compounds of Formula (HI), or a
pharmaceutically acceptable salt thereof, as defined herein.

15

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula (I) may also be used in association with the
veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or
other chemokines which bind to the IL-8 a and b receptors. Chemokine mediated
20 diseases for treatment, therapeutically or prophylactically, in animals include disease
states such as those noted herein in the Methods of Treatment section.

In compounds of Formula (I), R is suitably any functional moiety which
provides an ionizable hydrogen having a pKa of 10 or less, preferably from about 3 to
25 9, more preferably from about 3 to 7. Such functional groups include, but are not

limited to, hydroxy, carboxylic acid, thiol, -SR2 -OR2, -NH-C(0)R a , -C(0)NR6R7, a
substituted sulfonamides of the formula -NHS(0)2Rb, -S(0)2NHRo NHC(X2)NHRb.
or a tetrazolyl; wherein X2 is oxygen or sulfur, preferably oxygen. Preferably, the

functional group is other than a sulfonic acid, either directly or as a substituent group oh
30 the aryl, heteroaryl, or heterocyclic moiety ring, such as in SR2 or OR2- More
preferably R is OH, SH. or NHS(0)2Rb-

Suitably, R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring
has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less.

35

Suitably, R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6
and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring

- 5 -

WO 97/29743

PCTYUS96/13632

which ring may optionally contain an additional heteroatom which heteroatom is
selected from oxygen, nitrogen or sulfur. This heteroring may be optionally substituted
as defined herein.

5 Suitably R a is an alkyl, aryl, arylCt-4alkyl, heteroaryl, heteroarylC i-4alkyl,

heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally
substituted, as defined herein below.

Suitably, is a NR^Ry, alkyl, aryl, aryl C1.4 alkyl, aryl C2.4 alkenyl,
10 heteroaryl, heteroaryl C1.4 alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclic

C 1 .4 alkyl, a heterocyclic C2-4 alkenyl moiety, or camphor, all of which groups may be

optionally substituted one to three times independently by halogen; nitro;
halosubstituted C 1.4 alkyl, such as CF3; C1.4 alkyl, such as methyl; Cj_4 alkoxy, such
as methoxy; aryl; heteroaryl; heterocyclic; NRoC(0)R a ; C(0)NR^R-j, S(0>3H,
15 S(0) m 'R a (wherein m' is 0, 1 or 2), or C(0)OCi_4 alk y'- When R b is an aryl or

arylalkyl, preferably it is an optionally substituted phenyl, benzyl, or styryl. When R^
is a heteroaryl preferably it is an optionally substituted thiazole, optionally substituted
thienyl, optionally substituted quinolinyl or isoquinolyl ring, or pyridyl ring.

20 R9 is hydrogen or a C 1. 4 alkyl, preferably hydrogen. Suitably, when the

substituent group on the R^ moiety is NR9C(0)R a , then R a is preferably an alkyl
group, such as methyl.

Suitably Rc is hydrogen, alkyl, aryl, arylCi-4alkyl, arylCi-4alkenyl, heteroaryl,
25 heteroarylC 1 -4alkyl, heteroarylC 1 -4alkenyl, heterocyclic, or heterocyclic C 1 -4alky I, or
a heterocyclic Ci-4alkenyl moiety, all of which groups may be optionally substituted
one to three times independently by halogen, nitro, halosubstituted C 1 -4 alkyl, Ci-4
alkyl, C1-4 alkoxy, NRoC(0)R a , C(0)NR6R7, S(0)3H, or C(0)OCi-4 alkyl, wherein
Ro is hydrogen or a Ci-4 alkyl. Preferably, Rc is an optionally substituted phenyl.

30

When R is an OR2 or SR2 moiety it is recognized by one of skill in the art that
the aryl ring must, therefore, contain the required ionizable hydrogen. The aryl ring
may also be additionally substituted, independently, by one to three groups, which
groups may also contain an additional ionizable group, and which include but are not
35 limited to, halogen, nitro, halosubstituted Ci-4 alkyl, Ci-4 alkyl, C1.4 alkoxy, hydroxy,
SH, -C(0)NR6R7, -NH-C(0)R a , -NHS(0)2Rb, S(0)2NR6R7, C(0)OR8, or a
tetrazolyl ring.

-6-

WO 97/29743

PCT/US96/13632

In compounds of Formula (I), suitably R\ is suitably an electron withdrawing
moiety. R\ may be independently selected from hydrogen; halogen; nitro; cyano;
halosubstituted Ci-io alkyl, such as CF3; Ci-io alkyl. such as methyl, ethyl, isopropyl,
or n-propyl; C2-10 alkenyl; Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted
Ci-io alkoxy, such as trifluoromethoxy; azide; S(0)tR4, wherein t is 0, 1 or 2;
(CRgRg)q S(0)tR4; hydroxy; hydroxy substituted Ci-4alkyl, such as methanol or
ethanol; aryl, such as phenyl or naphthyl; aryl Ci-4 alkyl, such as benzyl; aryl C2-10
alkenyl ; aryloxy, such as phenoxy; aryl Ci-4 alkyloxy, such as benzyloxy; heteroaryl;
heteroarylalkyl; heteroaryl Ci-4 alkyloxy; heteroaryl C2-10 alkenyl; (CR 8 R 8 )qNR4R5;
C2-10 alkenyl-C(0)NR4R5; (CRgRg)qC(0)NR4R5; (CR 8 R 8 )qC(O)NR4Ri 0 ; S(0)3H;
S(0)3R 8 ; (CRgRg)q C(0)Ri 1, such as trifluromethyl ketone ; C2-10 alkenyl C(0)Ri 1,
C2-10 alkenylC(0)ORi l; (CRgRg)qC(0)ORi i, such as carboxy, methylcarboxylate or
phenylbenzoate; (CRgR 8 )qC(0)ORi2; (CR 8 R 8 )qOC(0)Ri l; (CRgRg)q NR4QO)Ri i;
(CRgRg)qNHS(0) 2 Ri3, (CRgRg)qS(0)2NR 4 R5; or two Ri moieties together may
form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring; and s is an integer having a
value of 1 to 3. The alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl,
heteroarylalkenyl, heterocyclic, heterocyclicalkyl, and heterocyclicalkenyl moieties may
all be optionally substituted as defined herein below. Preferably Ri is other than azido
or S(0)3R 8 . Rg is independently hydrogen or C \_4 alkyl, which may be branched or
straight.

When Ri forms a dioxybridge, s is preferably 1. When R\ forms an additional
unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system.
This naphthylene ring may be substituted independently, 1 to 3 times by the other Ri
moieties as defined above.

Suitably, R4 and R5 are independently hydrogen, optionally substituted C1-4
alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkyl, optionally
substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic,
heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S. The optionally substituted moieties are as defined
herein below.

RiO is suitably C 1-10 alkyl C(0)2R8, such as CH2C(0)2H or CH2C(0)2CH3.

WO 97/29743 PCT/US96/13632

Rl 1 is suitably hydrogen, optionally substituted C\ -4 alkyl, optionally
substituted aryl. optionally substituted aryl Ci-4 alkyl, optionally substituted heteroaryl,
optionally substituted heteroaryl Ci-4alkyl, optionally substituted heterocyclic, or
optionally substituted heterocyclic Ci-4alkyl. The optionally substituted moieties are as
5 defined herein below.

Rl2 is suitably hydrogen, optionally substituted C^.iq alkyl, optionally
substituted aryl or optionally substituted arylalkyl. The optionally substituted moieties
are as defined herein below.

,0

Preferably Rl is halogen, cyano, nitro, CF3, C(0)NR4R5. alkenyl C(0)NR4R5,
C(O) R4R10. alkenyl C(0)ORl2. heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or
S(0)NR4R5, and preferably R4 and R5 are both hydrogen or one is phenyl. A
preferred ring substitution for Rl is in the 4-position of the phenyl ring.

15

When R is OH, SH or NS02Rb than Rl is preferably substituted in the 3-
position, the 4- position or di-substituted in the 3,4- position. The substituent group is
suitably an electron withdrawing moiety. Preferably when R is OH, SH or NS02Rb»
than Rl is nitro, halogen, cyano, trifluoromethyl group, C(0)NR4R5-

20

When R is carboxylic acid, than Rl is preferably hydrogen, or Rl is preferably
substituted in the 4-position, more preferably substituted by trifluoromethyl or chloro.

In compounds of Formula (I), suitably Y is independently selected from
25 hydrogen; halogen; nitro; cyano; halosubstituted C 1 . 10 alkyl; C 1 - 10 alkyl; C2- 10

alkenyl; Ci-10 alkoxy; halosubstituted Ci- 10 alkoxy; azido; (CR 8 R 8 )qS(0) t R4,

wherein q is 0 or an integer having a value of 1 to 10; (CR 8 R8)q°R4'' hydroxy;

hydroxy Ci-4alkyl; aryl; aryl C 1-4 alkyl; aryloxy; arylQ-4 alkyloxy; aryl C210

alkenyl; heteroaryl; heteroarylalkyl; heteroaryl C 1 .4 alkyloxy; heteroaryl C2- 10
30 alkenyl; heterocyclic, heterocyclic C 1 -4alkyl; heterocyclicC2- 10 alkenyl;

(CR 8 R 8 )qNR4R5; C2-10 alkenyl C(0)NR4R5; (CR 8 R 8 )qC(0)NR4R5;

(CR 8 R 8 )qC(O)NR4Rl0; S(0)3R8; (CR 8 R 8 )qC(0)Rn; C2-10 alkenyl C(0)Rn;

C2-10 alkenyl C(0)ORu; (CR 8 R 8 )q C(0)ORi2; (CR 8 R 8 )qOC(0)R 1 1 ;

(CR 8 R 8 )qNR4C(0)Rn; (CR 8 R 8 )q NHS(0) 2 Rb. (CR 8 R 8 )qS(0) 2 NR4R 5 ;
35 CR 8 R 8 )qC(NR 4 )NR 4 R5; (CR 8 R 8 )q NR4C(NR 5 )Ri 1, or two Y moieties together may

form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring. When Y forms a

dioxybridge, s is preferably 1. When Y forms an additional unsaturated ring, it is

- 8 -

WO 97/291 '43

PCT/US96/13632

preferably 6 membered resulting in a naphthylene ring system. This naphthylene ring
may be substituted 1 to 3 times by another Y moiety, such as defined above.
Additionally all of the various aryl, heteroaryl and heterocyclic groups noted above, as
well as the R4, R5 and R\ \ substituent groups, may be optionally substituted as defined
5 herein in the specification below. Preferably Y is other than azido or S(0)3Rg. Rs is
independently hydrogen or Ci-4 alkyl.

Y is preferably a halogen, C1-4 alkoxy, optionally substituted aryl, optionally
substituted aryloxy, optionally substituted arylalkoxy, optionally substituted
10 arylalkyloxy, optionally substituted heteroarylalkyloxy, methylenedioxy, NR4R5,
thioCi-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C1-4 alkyl, or
hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen,
mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more
preferably these groups are mono or di-substituted in the 2'- position or 2'-, 3 -position.

15

While Y may be substituted in any of the 5 ring positions, preferably when R is
OH, SH, or NHS02Rb. Y is preferably mono-substituted in the 2 -position or 3'-
position, with the 4 - preferably being unsubstituted. If the ring is disubstituted, when R
is OH, SH, or NHS02Rb. substituents are preferably in the 2' or 3' position of a
20 monocyclic ring. While both Ri and Y can both be hydrogen, it is prefered that at least
one of the rings be substituted, preferably both rings are substituted.

In compounds of Formula (I), X is suitably oxygen or sulfur, preferably oxygen.

25 While not explicitly covered by Formula (I), (Ia-c), (II), (Ila-c), or (EH), another

aspect of this invention are the symmetrical bis compounds which are included for each
structure.

Compounds exemplified by this bis like structure include:
30 N-(Bis (2-hydroxy-4-nitro phenyl-N'-(dianisdine)diurea

4-Methylene bis(N-(2-chloro phenyl)-N'-(2-hydroxy 4-nitrophenyl)urea)

Exemplified compounds of Formula (I) include:
N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenylurea;
35 N-[5-Nitro-2-hydroxyphenyl]-N'-phenyl urea

3-Hydroxy-4-{ [(phenylamino)carbonyl]amino}benzamide
N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea

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2- { [(Phenylamino)carbonyl]amino } thiophenol
N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea
N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N'-phenyl urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea

5 N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea

N-(4-Nitro-2-(phenylsulfonylamino)phenyl)-N'-phenyl urea
N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea

10 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-trifluoromethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea
N-{2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea

15 N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(l-naphthyl)urea;
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitrophenyl)urea

20 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluorophenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifiuoromethoxyphenyl)urea

25 N-(2-Hydroxy-4-nitrophenyl) N'-(2-methylthiophenyl) urea

N-(2-Hydroxy-4-nitrophenyl) N'-(2-chloro 6-methyl phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2-sulfoxymethyl phenyl) urea
N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-(2-bromo phenyl) urea
N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-bromophenyl) urea

30 N-(4-Trifluoromethyl-2-hydroxy phenyl) N'-(2-phenyl phenyl) urea
N-(4-Carbomethoxy 2-hydroxy phenyl) N'-(2-phenyl phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2,3-dichloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2,4-dichloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2-chloro phenyl) urea

35 N-(2-Hydroxy-4-nitrophenyl) N'-(2,4-dibromophenyl) urea
N-(2-Hydroxy-l-napthyl)-N'-(2-bromophenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea

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N-(2-Hydroxy-4-nitrophenyl)-N'-(3-chloro-2-methoxyphenyl) urea
N-(2-Hydroxy-4-nitrophenyI)-N'-(2-methylphenyl) urea
N-[4-(Benzylamino)carbonyl-2-hydroxyphenyI]-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenoxyphenyl) urea
5 N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromophenyl) urea
N-(2-Hydroxy-3-napthyl)-N'-(2-bromophenyl) urea
N-(3,4-Difluoro-2-hydroxyphenyl)-N'-(2-bromophenyl) urea
N-(2- Hydroxy 4-phenylphenyl)-N'-(2-bromophenyl) urea
N-(2-Hydroxy-4-methylphenyl)-N'-(2-bromophenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylaminophenyl) urea
N-(2-Hydroxy-3-carboxyphenyl)-N'-(2-bromophenyl) urea
N-(2-Sulfhydryl-4-bromophenyl)-N'-(2-bromophenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-iodophenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl) thiourea
N-[(2-Phenylsulfamido)-4-cyanophenyl]-N'-(2-bromophenyl) urea
N-(2-(Arrunosulfonarnidophenyl)phenyl)-N'-(2-brornophenyl) urea
N-(2-{Aminosulfonylstyryl) phenyl)-N'-(2-bromophenyl) urea
2-[(3,4-Di-methoxyphenylsuIfonyl)amino]phenyl)-N'-(2-bromophenyl) urea
N-(2-[(4-Acetairudophenylsulfonyl)amino]phenyl)-N'-(2-brornophenyl) urea
N-(2-(Aminosulfonyl (2-thiophene)phenyl)-N'-(2-bromophenyl) urea
N-(2-(Aminosulfonyl (3-tolyl) phenyl)-N'-(2-bromophenyl) urea
N-(2-(Aminosulfonyl (8-quinolinyl))phenyl)-N'-(2-bromophenyl) urea
N-(2-(Aminosulfonyl benzyl) phenyl)-N'-(2-bromophenyl) urea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea
N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl]urea
N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenylurea
N-[2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl]urea
N-[2-Hydroxy-3-chlorophenyl]-N'-t2-bromophenyl]urea
N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl]urea
N-[2-Hydroxy-3,4-diphenyl-phenyl]-N'-f2-bromophenyl]urea
N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-glycincarbonylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3 ,5-dichlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea

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N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea
5 N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea

N-[2-Hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N'-[2-bromophenyl] urea
10 N-[2-Hydroxy-3-cyano-4-methylphenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-4-carbophenyl phenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea

N- [3-Benzy loxy -2-hy droxy pheny 1]-N' - [2-bromopheny 1] urea

(E)-N-[4-[2-(Methoxycarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea
15 (E)-N-[3-[2-(Methoxycarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea-

N'-[2-bromophenyilurea
(E)-N-[3-[2KAminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N'-

[2-bromophenyl]urea

(E)-N-[4-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-brornophenyl]urea-N'-

20 [2-bromophenyl]urea

N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl]urea
N-[4-Aminocarbonyl-2-hydroxyphenyl]-N'-[2-bromophenyl]urea
N-(2-Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea

25 N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea

N-[24[[2KTrifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-brornophenyl)urea
N-(2-Bromophenyl)-N'-[2-dimethylarrunosulfonylarnino]phenyl]urea
N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea
N42-[(2-Acetarnido-4-methyltruazol-5-yl)sulfonylamino]phenyl]-N'-(2-

30 bromophenyl)urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N , -[2,3-dichlorophenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl] urea
35 N-[2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl]urea

N-[2-Hydroxyphenyl]-N'-[2-bromophenyll urea

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N-[Trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-phenyIphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea

N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(3.5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-brornophenyl)urea
N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl) urea
N-[[2-( lS)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[[2KlR)-10-Camphorsulfonylarnino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)suIfonylamino]phenyl-N'-(2-

bromophenyl)urea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-iodophenyl)urea
N-(2-Hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyI] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2-phenylphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-5-ethylsulfonylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2-

bromophenyl)urea
N-[2-(Aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl) urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4 dimethoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea

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N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-5-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea;
N-[2-Hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea;
1 , 1 '-(4-Methyl-2-phenylene)bis[2-thio-3-tolylurea]
5 N-(2-Carboxyphenyl)-N'-phenylurea

N-(2-Hydroxy-4-nitrophenyl)-N'-phenylurea

1- (2-Carboxyphenyl)-3-(4-chlorophenyl)urea

2- (3,4-Dichlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid
2-(4-Chlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid

10 l-(p-Anisyl)-3-(2-carboxyphenyl)urea

l-(2-Carboxyphenyl)-3-(3-fluorophenyl)urea

l-(2-Carboxyphenyl)-3-(3-chlorophenyl)urea

l-(m-Anisyl)-3-(2-carboxyphneyl)urea

l-(o-Anisyl)-3-(2-carboxyphenyl)urea
15 l-(2-Carboxyphenyl)-3-(3,4-dichlorophenyl)urea

l-(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea

N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N'-phenylurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(4-nitrophenyl)urea

N-[2-t2-(4-ChloroO-aminophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
20 N-[2-(3-Aminophenyl)sulfonylaminophenyl]-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(3-trifluoromethyphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(2-phenylphenyl)urea

25 N-(2-Hydroxy-3-nitrophenyl)-N'-(2,3dichlorophenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(4-phenylphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(2,4-dimethoxyphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-methoxyphenyl)urea

30 N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-phenyiphenyl)urea

N-(2-Benzenesulfonylamino^-cyanophenyl)-N'-(3-trifluoromethylphenyl)urea
N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2,3dichlorophenyl)urea
N-(2-Hydroxy-4-amidinophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3,4-dichloro phenyl) N'( phenyl) urea

35 N-(2-Hydroxy 4-cyano phenyl) N'( phenyl) urea

N-(2-Hydroxyphenyl 3-carboxylic acid)N'( phenyl) urea
N-(2-Hydroxy-3-nitrophenyl)-N'-phenylurea

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N-(2-Hydroxy-3-cyano phenyl ) N'(phenyl) urea
N-(2-Hydroxy-3-cyano-4-chlorophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-fluorophenyl)-N'-(phenyl)urea
N-(2-Hydroxy-3,4-difluorophenyl)-N'-(phenyl)urea

5 N-(2-(Benzylsulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea

N-[2-(Phenylsulfonylamino)-4-trifluoromethylphenyl]-N'-(2,3-dichlorophenyl)urea
N-[2-(3-Pyridinesulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea
N-[2-(5-Isoquinolinesulfonylamino)-4-cyanophenyl]-N'-(2,3-dichiorophenyl)urea
N-[2-{Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-chlorophenyl)urea

10 N-[(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-fluoro phenyl) urea

N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-thiomethylphenyL)urea
N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-trifluoromethoxyphenyl)urea
N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-trifluoromethylphenyI)urea
N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methylphenyl) urea

15 N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-methoxy 3-chloro phenyl) urea
N-[2-(4-cyanophenyl)-N'-(3-fluoro phenyl) urea

N-(2-Thiophenesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea

N-[(2-Pyrid-2-yl)thiophene-5-sulfonyIamino-4-cyanophenyl]-N'-(2,3-dichiorophenyl)urea

N-[(2-Acetamino^-methyl-5-thiazolesulfonylarnino-4-cyanophenyl]-N'-(2,3-

20 dichlorophenyDurea

N-((2-Aminosulfonylphenyl) 4-cyano phenyl) N'-(2-methyl 3-chloro phenyl) urea
N-(2-Benzenesulfonylamino-3-cyanophenyl)-N'-(2,3dichlorophenyl)urea
N-[(Benzylsulfonylamino)-5-cyanophenyl]-N'-(2,3-dichlorophenyl)urea
N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-nitrophenyl)urea

25 N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-nitrophenyl)urea
N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-aminophenyl)urea
N-[(2-Phenylsulfonylamino)-4-cyanophenyl)-N'-(2-aminophenyl)urea
N-(2-(2-Pyridinesulfonylarnino-4-cyanophenyl)-N , -(2,3-dichlorophenyl)urea
N-(2-Benzenesulfonylamino-3-trifluoromethylphenyl-N'-(2,3-dichlorophenyl)urea

30 N-(4-Benzenesulphonylthiophene-2-sulphonylamino-4-cyanophenyl)-N'-(2,3-
dichlorophenyl)urea

N-(2-Trifluoromethylbezenesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2,3-methylenedioxyphenyl)urea
N-[2-(2-Nitrophenylthio)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea
35 N-(2-Hydroxy-3-trifluoromethylphenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-3-trifluoromethylphenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-benzylphenyl)urea

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N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylthiomethyl)phenyl]urea

N-(2-Hydroxy-4-nitro phenyi)-N'-[2-(phenyloxymethyl)phenyl]urea

N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylethyl)phenyl]urea

N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(4-trifluorophenyl)phenyl]urea

N-(2-Hydroxy-3-trifloromethylphenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-acetoxyphenyI)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(2-cyanophenylthio)phenyl]urea

N-(2-Hydroxy-3-trifluoromethylphenyl)-N'-(2-chlorophenyl)urea

N-(2-Hydroxyethyl)-N'-(2-hydroxy-4-nitrophenyl)urea

N-2-(Benzyoxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(2-Thienylsulfonylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2-bromophenyl)urea

N-(2-Benzylsulfonylamino-4-nitrophenyI)-N'-(2-bromophenyl)urea

N-(2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2,3dichlorophenyl)urea

N-[2-(3-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(4-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(Methoxycarbonylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(Methylsulfonylamino)-4-nitrophenyl]-N'-(2-bromophenyl)urea

N-[2-(Propylsulfonylamino)-4-nitrophenyl)-N'-(2-bromophenyl)urea

N-[2-(Propylsulfonylamino)-4-nitrophenyl]-N'-(2,3-dichJorophenyl)urea

N-[[(2-acetamino-4-methyl-5-thiazolyl)suifonylamino]-4-nitrophenyl]-N'-(2,3-

dichlorophenyl)urea

N-[2-(3-Pyridinesulfonylamino)-4-nitrophenyl]-N'-(2,3-dichlorophenyl)urea

N-[2-(3-Pyridinesulfonylamino)-4-nitrophenyl]-N'-(2-bromophenyl)urea

N-[2-(Methylsulfonylamino)-4-nitrophenyl]-N'-(2,3-dichlorophenyl)urea

N-{2-Hydroxyeth-l-yloxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-benzylaminophenyl)urea

N'-[2-(2-Pyridylmethoxy)phenyl]-N'-(2-Hydroxy-4-nitrophenyl)urea

N-[2-(2-Methoxycarbonylbenzyloxyphenyl]-N-(2-hydroxy-4-nitrophenyl)urea

N-[2-(2-Carboxybenzyloxy)phenyl)-N'-C2-hydroxy-4-nitrophenyl)urea

N-[2-(Benzoylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

Additionally exemplified compounds of Formula (I) include:
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(benzyloxy)phenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(2-pyridylmethyloxy)phenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(3-pyridylmethyloxy)phenyl)urea

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N-{2-Hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea

N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-4-trifluorosulfonylphenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-<2-bromophenyl)urea

N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2.3-dichlorophenyl)urea

N-(2-Hydroxy-4-trifluorosulfonylphenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2,3-dichlorophenyl)urea

Prefered compounds of Formula (I) include:

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methylthiophenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-hydroxy 4-nitro phenyl) N'-(2-chloro phenyl) urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-3-chlorophenyl)urea

N-(2-hydroxy 4-nitro phenyl) N'-{2-phenyloxy phenyl) urea

N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea

N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N'-(2-bromophenyl)urea

N-(3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2-bromophenyl)urea

N-(3-Cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea

N-(2-Hydorxy-4-cyanophenyl-N*-(2,3-dichlorophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea

N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea

N-(4-Cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea

N-(3-Trifluoromethyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea

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N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea

N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea

N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea

N-(2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea
5 (E)-N-[3-[(2-Aminocarbonyl)ethenyI]-2-hydroxyphenyl]-N'-(2-bromophenyl)urea

N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-phenylphenyl)urea

N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Hydroxy-5-nitrophenyl)-N'-(2,3-dichlorophenyl)urea
10 N-(2-Hydroxy-3-cyanophenyl)-N'-(2,3 dichlorophenyl)urea

As used herein, "optionally substituted" unless specifically defined shall mean
such groups as halogen, such as cyano, nitro, fluorine, chlorine, bromine or iodine;
hydroxy; hydroxy substituted Ci-lOalkyl; Ci-io alkoxy, such as methoxy or ethoxy;

15 S(0)m' Ci-io alkyl, wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or
methyl sulfonyl; amino, mono & di -substituted amino, such as in the NR4R5 group;
NHC(0)FU; C(0)NR4R5; C(0)ORi y, S(0)2NR4R5i NHS(0)2Rl3, Ci-io alkyl, such
as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted Ci-io alkyl, such CF3; an
optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such

20 as benzyl or phenethyl, optionally substituted heterocylic, optionally substituted

heterocylicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl
alkyl, wherein these aryl, hetroaryl, or heterocyclic moieties may themselves be
optionally substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl;
Ci-io alkoxy; S(O) m 'Ci-i0 alkyl; amino, mono & di-substituted amino, such as in the

25 NR4R5 group; C1-10 alkyl, or halosubstituted Ci-io alkyl, such as CF3.

RB is suitably C 1.4 alkyl, halosubstituted Q-4 alkyl, aryl, aryl Ci-4alkyl,
heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl.

Another aspect of the present invention are the novel compounds of Formula
30 (II), or a pharmaceutical^ acceptable salt thereof, as described below, which are also
useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof.
This invention also relates to the pharmaceutical compositions comprising a compound
of Formula (II) and a pharmaceutically acceptable diluent or carrier. Compounds of
Formula (II) are also useful for treating a chemokine mediated disease, wherein the
35 chemokine is one which binds to an IL-8 a or b receptor and which method comprises
administering an effective amount of a compound of Formula (Il)-or a pharmaceutically
acceptable salt thereof.

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Compounds of Formula (II) are represented by the structure:

(II)
wherein

X is oxygen or sulfur;

R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
Ci-ioalkoxy; azide; S(0)tR4; (CRgRg)q S(0)tR4; hydroxy; hydroxy substituted
Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;
heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10
alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(0)NR4Rs; C2-10 alkenyl C(0)NR4R.5;
(CRgRg)q C(O)NR4Rl0; S(0)3R8; (CRgRg)q C(0)Rn; C2-10 alkenyl C(0)Rn;
C2-10 alkenyl C(0)ORi 1; (CRgRg)q C(0)ORi 1; (CRgRg)q OC(0)Ri i ;
(CRgRg)qNR4C(0)Rn; (CRgRg)q C(NR4)NR4R 5 ; (CRgRg)q NR4C(NR 5 )Ri h
(CRgRg)q NHS(0)2Ri3; (CRgRg)q S(0)2NR4R5, or two Rl moieties together may
form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3 ;

R4 and R5 are independently hydrogen, optionally substituted C\-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic,
heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)qS(0) t R4,
(CRgRg)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Ci-4 alkyl;
aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl C1-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CRgRg)qNR4R5; C2-10 alkenyl
C(0)NR4R5; (CRgRg)qC(0)NR4R5; (CRgRg)q C(O)NR4Rl0; S(0)3Rg;

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(CR 8 R 8 )qC(0)R 1 1 ; C2- 10 alkenylC(0)R 1 1 ; (CR 8 R 8 )qC(0)OR 1 1 ;

C2-10alkenylC(O)ORn; (CRgR 8 )qOC(0) Rji; (CR 8 Rg)qNR4C(0)Ri i;

(CR 8 R 8 )q NHSCO) 2 Rb; (CR 8 R 8 )q S(0) 2 NR 4 R 5 ; (CR 8 R 8 )qC(NR 4 )NR4R 5 ;

(CR 8 R 8 )q NR 4 C(NR5)Ri y, or two Y moieties together may form 0-(CH2)sO- or a

5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,

heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally

substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;

R 8 is hydrogen or Ci-4 alkyl;

RlOisCi-ioalkyl C(0)2R8;

Rl 1 is hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl,

optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally
substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicCi-4alkyl;

Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted
arylalkyl;

Rl3 is suitably C1.4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl,
heterocyclic, or heterocyciicCi-4alkyl;

Rb is NR5R7, alkyl, aryl, aryl C\_4 alkyl, aryl C 2 -4 alkenyl, heteroaryl, heteroaryl
C\_4 alkyl, heteroarylC 2 -4 alkenyl, heterocyclic, heterocyclic Cj_4 alkyl,
heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally

substituted;
E is optionally selected from

the asterix * denoting point of attachment of the ring, with at least one E being present;
or a pharmaceutically acceptably salt thereof.

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Suitably, the variables for Formula (II), such as X, R, Rl, R4 . R5, R6, R7. R8<
R9, Y, R a , Rb, Rc. n. rn, and s terms, etc. are as defined in Formula (I) above. The E
ring denoted by its point of attachment through the asterix (*) may optionally be
5 present. If if it is not present the ring is a phenyl moiety which is substituted by the R
and Rl terms as shown. At least one E ring is necessary. The E ring may be substituted
by the Rl or Y moiety in any ring, saturated or unsaturated, and is shown for purposes
herein substituted only in the unsaturated ring(s).

10 Another aspect of the present invention are the novel compounds of Formula

(Ha), (lib) and (lie) which are similar to those described herein for Formulas (la), (lb)
and (Ic) but which require one of the two phenyl rings to posses an E ring.

Suitably, for compounds of Formula (Ila-c), the variables are as defined herein
for Formulas (I) and (II).

15

Compounds of Formula (Ha) are represented by the structure:

wherein

X is oxygen or sulfur;
20 R is -NHS(0)2R D ;

R a is an alkyl, aryl, arylCi-4alkyl, heteroaryl, heteroaryl Ci-4alkyl, heterocyclic, or a

heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted;
Rb is a NR6R7, alkyl, aryl, arylCi-4alkyl, aryl C2-4alkenyl, heteroaryl,

heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclic
25 C i-4alkyl, or a heterocyclic C2-4alkenyl moiety, camphor, all of which may be

optionally substituted one to three times independently by halogen; nitro;
halosubstituted C1-4 alkyl; Q-4 alkyl; Q-4 alkoxy; NRQC(0)R a ; S(0) m -R a ,

C(0)NR6R7, S(0)3H, or C(0)OCi-4 alkyl;

R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together
30 with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur, which ring may be optionally substitued;

R9 is hydrogen or a Ci-4 alkyl, preferably hydrogen;

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Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted Ci-10 alkyl; C2-10 alkenyl; Ci-10 alkoxy; halosubstituted
Ci-ioalkoxy; azide; S(0)tR4; (CRgRg)q S(0)tR4; hydroxy; hydroxy substituted
Ci-4alkyl; aryl; aryl C1.4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;
heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-lO
alkenyl; (CR 8 R 8 )q NR4R5; (CR 8 R 8 )q QO)NR4R5; C2-10 alkenyl C(0)NR4R 5 ;
(CR 8 R 8 )q C(O)NR4Rl0; S(0) 3 R 8 ; (CR 8 R 8 )q C(0)Ri 1; C2-10 alkenyl C(0)Rn;
C2-IO alkenyl C(0)ORi 1; (CR 8 Rg)q C(0)ORi 1; (CR 8 R 8 )q OQO)Ri i ;
fCR 8 R 8 )qNR4C(0)Rl 1; (CR 8 R 8 )q C(NR 4 )NR 4 R 5; (CR 8 R 8 )q NR^NRs)!^ h
(CR 8 R 8 )q NHS(0) 2 Ri3; (CR g R 8 )q S(0) 2 NR4R 5 , or two R\ moieties together may
form 0-(CH 2 )sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci- 4 alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci- 4 alkyl, heterocyclic,
heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C 2 -10
alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgR 8 )qS(0) t R4,
(CRgRg)qOR4; hydroxy; hydroxy substituted Ci_4alkyl; aryl; aryl C1-4 alkyl;
aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl C 1-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC 2 -10 alkenyl; (CRgRg)qNR4R5; C2-10 alkenyl
C(0)NR4R5; (CRgRg)qG(0)NR4R5; (CRgRg)q C(O)NR4Rl0; S(0)3R8;
(CRgRg)qC(0)Ri 1; C2-10 alkenylC(0)R 1 1 ; (CRgRg)qC(0)ORi 1;
C2-10alkenylC(O)ORi 1; (CRgRg)qOC(O) Rn; (CR 8 Rg)qNR4C(0)Rn;
(CRgRg)q NHS(0) 2 R b ; (CRgR 8 )q S(0) 2 NR 4 R 5 , (CR 8 Rg)qC(NR4)NR 4 R5;
(CRgR 8 )q NR4C(NR5)Ri 1; or two Y moieties together may form 0-(CH2)sO- or a
5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,
heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally
substituted;

q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;

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m is an integer having a value of 1 to 3;
R.8 is hydrogen or Ci-4 alkyl;
RlO is Ci-io alkyl C(0)2R8;

RH is hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl,
5 optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally

substituted heteroarylCi-4aikyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC l -4alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted

arylalkyl;

10 Rl3 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl,
heterocyclic, or heterocyclicC i~4alkyl;
E is optionally selected from

the asterix * denoting point of attachment of the ring; with the proviso that at least one
15 E ring being present;

or a pharmaceutically acceptably salt thereof.

Formula (lib) compounds contain the R functionality of X1R2 wherein R2 is R2
is a substituted aryl, heteroaryl, or heterocyclic ring which ring has a functional moiety
20 providing the ionizable hydrogen having a pKa of 10 or less; and the remaining
variables as defined above for compounds of Formula (I) and (II).

Formula (lie) compounds contain the R functionality X^H, wherein X\ is
oxygen or sulfur and the remainder of the variables are as defined in Formula (I) and
25 (II) above.

Exemplified compounds of Formula (II) include:
N-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea;
N-[ 1 -hydroxy fluorene]-N'-[2-bromophenyl] urea;
30 N-[3-hydroxy-9,10-anthraquinon-2-yl]-N'-[2-bromophenyl] urea

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Another aspect of the present invention are the novel compounds of Formula

(III), or a pharmaceutically acceptable salt thereof, as described below, which are also

useful in inhibiting the binding of IL-8 to its receptors in a mammal in need thereof.

This invention also relates to the pharmaceutical compositions comprising a compound

5 of Formula (III) and a pharmaceutically acceptable diluent or carrier. Compounds of

Formula (III) are also useful for treating a chemokine mediated disease, wherein the

chemokine is one which binds to an EL-8 a or b receptor and which method comprises

administering an effective amount of a compound of Formula (HI) or a

pharmaceutically acceptable salt thereof.

10 Compounds of Formula (IE) are represented by the structure:

(Y)n

S N"^N

H H

wherein

X is oxygen or sulfur;
R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
15 Ri is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;

halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted

Ci-ioalkoxy; azide; S(0) t R4; (CRgRg)q S(0) t R4; hydroxy; hydroxy substituted

Ci_4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci-4 alkyloxy;

heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;
20 heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi_4alkyloxy; heterocyclicC2-10

alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(0)NR4Rs; C2-10 alkenyl C(0)NR4R5;

(CR 8 Rg)q C(O)NR4Rl0; S(0)3R8; (CR 8 R 8 )q C(0)Ri 1; C2-10 alkenyl C(0)Ri 1;

C2-10 alkenyl C(0)ORi 1; (CRgRg)q C(0)ORi 1; (CR 8 Rg)q OC(0)Ri i ;

(CR 8 Rg)qNR4C(0)Ri 1; (CR 8 R 8 )q C(NR4)NR4R 5 ; (CRgRg)q NR4C(NR 5 )R 1 { ,
25 (CRgRg)q NHS(0) 2 Ri3; (CRgRg)q S(0)2NR4Rs, or two Ri moieties together may

form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,

arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
30 s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted Ci -4 alkyl, optionally

substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted

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heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic,
heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S;
Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Cj-io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci- 10 alkoxy; azide; (CRgRg)qS(0) t R4,
(CRgR8)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Ci-4 alkyl;
aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl Ci-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CR 8 Rg)qNR4R5; C2-10 alkenyl
C(0)NR4R5; (CR 8 R 8 )qC(0)NR4R5; (CRgRg)q C(O)NR4Ri0; S(0)3R 8 ;
(CR 8 R 8 )qC(0)Ri 1; C2-10 alkenylC(0)R 1 1 ; (CR 8 R 8 )qC(0)ORl 1;
C2-10alkenylC(O)ORi 1; (CR 8 R 8 )qOC(0) Ri 1; (CRgRg)qNR4C(0)Ri 1;
(CR 8 Rg)q NHS(0) 2 R b ; (CR 8 R 8 )q S(0)2NR 4 R 5 ; (CR 8 Rg)qC(NR4)NR4R 5 ;
(CRgRg)q NR4C(NR5)Ri j; or two Y moieties together may form 0-(CH2)sO- or a

5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,
heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally
substituted;

n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;

R 8 is hydrogen or Ci-4 alkyl;

R 10 is C 1 . 10 alkyl C(0)2R8;

Rl 1 is hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl,

optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally
substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC i-4alkyl;

Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted
arylalkyl;

Rl3 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl,

heterocyclic, or heterocyclicC i-4alkyl;
R D is NR6R7, alkyl, aryl, aryl C\_4 alkyl, aryl C2.4 alkenyl, heteroaryl, heteroaryl

Ci_4 alkyl, heteroaryIC2-4 alkenyl, heterocyclic, heterocyclic C1.4 alkyl,

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WO 97/29743

PCTYUS96/13632

heterocyclic C2.4 alkenyl, or camphor, all of which groups may be optionally

substituted;
E is optionally selected from

10

15

20

the asterix * denoting point of attachment of the ring;
or a pharmaceutically acceptably salt thereof.

Suitably, the variables, etc. for Formula (HI) are the same as those defined for
Formula (I) above, such as for example the R, Rj and Y variables. Suitably the E term

is the same as previously defined for Formula (II).

Exemplified compounds of Formula (III) include:
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea; and
N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea.

Another aspect of the present invention is the novel compounds of Formula (la),
a subset of compounds of Formula (I) useful for treating a chemokine mediated disease
as defined herein. This invention also relates to the pharmaceutical compositions
comprising a compound of Formula (la) and a pharmaceutically acceptable diluent or
carrier.

The compounds of Formula (la) are represented by the strucuture:

wherein

X is oxygen or sulfur;

R a is an alkyl, aryl, arylCi-4alkyl, heteroaryl, heteroaryl Ci-4alkyl, heterocyclic, or a
heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted;

Rb is a NR6R7, alkyl, aryl, arylCi-4alkyl, aryl C2-4alkenyl, heteroaryl,

heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclic

NHS(0) 2 Rb

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Ci-4alkyl, or a heterocyclic C2-4alkenyl moiety, camphor, all of which may be

optionally substituted one to three times independently by halogen; nitro;
halosubstituted C1-4 alkyl; Cl-4 alkyl; C\-4 alkoxy; NR9C(0)R a ; S(0) m 'R a ,

C(0)NR6R7, S(0)3H, or C(0)OCi-4 alkyl;

R6 and R7 are independently hydrogen, or a Ci_4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur, which ring may be optionally substitued;

R9 is hydrogen or a Cl-4 alkyl, preferably hydrogen;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted C i-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
Ci-ioalkoxy; azide; S(0)tR4; (CRgRg)q S(0) t R4; hydroxy; hydroxy substituted
Ci-4alkyl; aryl; aryl C1.4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Cl-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1-4 alkyloxy;
heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10
alkenyl; (CR 8 R 8 )q NR4R5; (CR 8 R 8 )q C(0)NR4R5; C2-10 alkenyl C(0)NR4R5;
(CR 8 R 8 )q C(O)NR4Rl0; S(0)3R8; (CR 8 R 8 )q C(0)Ri 1; C2-10 alkenyl C(0)Rl 1;
C2-10 alkenyl C(0)ORi 1; (CR 8 R 8 )q C(0)ORi 1; (CR 8 R 8 )q OC(0)Ri i ;
(CR 8 R 8 )qNR4C(0)Ri 1; (CR 8 R 8 )q C(NR4)NR4R 5 ; (CR 8 Rg)q NR 4 C(NR 5 )R 1 h
(CR 8 R 8 )q NHS(0) 2 Ri3; (CR 8 R 8 )q S(0) 2 NR4R5, or two Rl moieties together may
form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci_4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic,
heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci- 10 alkoxy; azide; (CR 8 R 8 )qS(0) t R4,
(CR 8 R 8 )qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Q.4 alkyl;
aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl Cl-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CR 8 R 8 )qNR4Rs; C2-10 alkenyl
C(0)NR4R5; (CRgRg)qC(0)NR4R5; (CR 8 R 8 )q C(O)NR4Rl0; S(0) 3 R 8 ;

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WO 97/29743 PCT/US96/13632

(CR 8 R8)qC(0)Rn; C2-10 alkeny!C(0)Ri 1; (CR 8 R8)qC(0)ORi 1;

C2-t0alkenylC(O)ORl l; (CR 8 R 8 )qOC(0) Ri 1; (CR 8 R 8 )qNR4C(0)Rn;

(CR 8 R 8 )q NHS(0) 2 Rb; (CR 8 R 8 )q S(0) 2 NR 4 R 5 ; (CR 8 R 8 )qC(NR 4 )NR 4 R 5 ;

(CR 8 R 8 )q NR4C(NR5)Rn; or two Y moieties together may form 0-(CH2)sO- or a
5 5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,

heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally

substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
10 m is an integer having a value of 1 to 3;
R 8 is hydrogen or Ci-4 alkyl;
RlO is Ci-io alkyl C(0)2R8;

Rl 1 is hydrogen, optionally substituted C 1-4 alkyl, optionally substituted aryl,

optionally substituted aryl Ci- 4 alkyl, optionally substituted heteroaryl, optionally
1 5 substituted heteroary 1C 1 - 4 alkyl, optionally substituted heterocyclic, or optionally

substituted heterocyclicC i-4alkyl;
Rl2 is hydrogen, Ci-10 alkyl, optionally substituted aryl or optionally substituted
arylalkyl;

Rl3 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl,
20 heterocyclic, or heterocyclicC i-4alkyl;

or a pharmaceutically acceptably salt thereof.

Suitably, the variables for Formula (la) are the same as those defined for
Formula (I) above, such as for examples the R, Ri„ and Y variables. A preferred ring

25 substitution for the Rl variable is monosubstituted in the 3-position, or the 4- position,
or di-substituted in the 3,4- position. The substituent group is suitably an electron
withdrawing moiety. Preferably Rl is nitro, halogen, cyano, trifluoromethyl group, or

C(0)NR4R5-

While Y may be substituted in any of the 5 ring positions, preferably the ring
30 with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4-

preferably being unsubstituted. If the ring is di-substituted, substituents are preferably
in the 2'-, 3'- positions of a monocyclic ring. While both Rl and Y can both be
hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings
are at least mono-substituted, i.e. n amd m are each equal to 1 or more.
35 Y is more preferably a mono-substituted halogen, disubstituted halogen, mono-

substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, preferably these
groups are substituted in the 2'- position or 2'-,3'-position.

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Exemplified compounds of Formula (la) are
N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea
N-[(2-Phenylsulfamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-(Amino sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea
2-[(3,4 Di-methoxyphenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea
N-(2-[(4-Acetamidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sulfonyl (3-tolyl) phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sulfonyl (8-quinolinyl)) phenyl) N'-(2-bromo phenyl) urea
N-(2-( Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl) urea
N-[2-[[[2-(Trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-bromophenyl)urea
N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl]urea
N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea
N-[2-[(2-Acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-

bromophenyl)urea

N-[2-[(2,3-Dichlorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea

N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyt)urea

N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea

N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea

N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl) urea

N-[[2-(lS)-10-Camphorsulfonylamino]phenyl]-N-(2-bromophenyl)urea

N-[[2-(lR)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea

N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-

bromophenyl)urea

N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2-

bromophenyl)urea
N-[2-(aminosulfonyl phenyl)-3-aminophenyl] N'-(2-bromo phenyl) urea
N-[2-[2-(4-Crdoro-3-arninophenyl)sulfonylarnino]phenyl]-N'-(2-bromophenyl)urea
N-[2-(3-Aminophenyl)sulfonylaminophenyl]-N'-(2-bromophenyl)urea
N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-phenylphenyl)urea
N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(3-trifluoromethylphenyl)urea
N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2,3dichlorophenyl)urea
N-[2-(Benzylsulfonylamino)-4-cyanophenyl]-N*-(2,3-dichlorophenyl)urea
N-[2-(Phenylsulfonylamino)-4-trifluoromethylphenyl]-N'-(2,3-dichlorophenyl)urea

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N-[2-(3-Pyridinesulfonyiamino)-4-cyanophenyl]-N'-(2,3-dichIorophenyl)urea
N-[2-(5-Isoquinolinesulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea
N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-chlorophenyl)urea
N-[(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-fluoro phenyl) urea
N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-thiomethylphenyl)urea
N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-trifluoromethoxyphenyl)urea
N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-trifluoromethylphenyl)urea
N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methylphenyl) urea
N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-methoxy 3-chloro phenyl) urea
N-[2-(4-cyanophenyl)-N'-(3-fluoro phenyl) urea

N-(2-Thiophenesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
N-[(2-Pyrid-2-yl)thiophene-5-sulfonylamino-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea
N-[(2-Acetamino-4-methyl-5-thiazolesulfonylarnino-4-cyanophenyl]-N'-(2,3-
dichlorophenyl)urea

N-((2-aminosulfonylphenyl) 4-cyano phenyl) N'-(2-methyl 3-chloro phenyl) urea

N-(2-benzenesulfonylamino-3-cyanophenyl)-N'-(2,3dichlorophenyl)urea

N-[(Benzylsulfonylamino)-5-cyanophenyl]-N'-(2,3-dichlorophenyl)urea

N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-nitrophenyl)urea

N-t(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-nitrophenyl)urea

N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-aminophenyl)urea

N-[(2-Phenylsulfonylamino)-4-cyanophenyl)-N'-(2-aminophenyl)urea

N-(2-(2-pyridinesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Benzenesulfonylamino-3-trifluoromethylphenyl-N'-(2,3-dichlorophenyl)urea

N-(4-Benzenesulphonylthiophene-2-sulphonylamino-4-cyanophenyl)-N'-(2,3-
dichlorophenyl)urea

N-(2-Trifluorornethylbezenesulfonylarnino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea

N-[2-(2-Thienylsulfonylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2-bromophenyl)urea

N-(2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2-bromophenyl)urea

N-(2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2,3dichJorophenyl)urea

Another aspect of the present invention is the novel compounds of Formula (lb),
a subset of compounds of Formula (I) useful for treating a chemokine mediated disease.
This invention also relates to the pharmaceutical compositions comprising a compound
of Formula (lb) and a pharmaceutically acceptable diluent or carrier.

The compounds of Formula (lb) are represented by the structure:

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WO 97/29743

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n(Y)

m

(lb)

wherein

X is oxygen or sulfur;
Xi is oxygen or sulfur;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
Ci-ioalkoxy; azide; S(0) t R4; (CR 8 R 8 )q S(0) t R4; hydroxy; hydroxy substituted
Ci-4alkyl; aryl; aryl C1.4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1.4 alkyloxy;
heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10
alkenyl; (CR 8 R 8 )q NR4R5; (CR 8 R 8 )q C(0)NR4R5; C2-10 alkenyl C(0)NR4Rs;
(CR 8 R 8 )q C(O)NR4Rl0; S(0)3R8; (CR 8 R 8 )q C(0)Ri 1; C2-10 alkenyl C(0)Ri 1;
C2-10 alkenyl C(0)ORl 1; (CR 8 R 8 )q C(0)ORi 1; (CR 8 R 8 )q OC(0)Ri i ;
(CR 8 R 8 )qNR4C(0)Ri 1; (CR 8 R 8 )q C(NR4)NR 4 R 5 ; (CR 8 R 8 )q NR4C(NR 5 )R! t ;
(CR 8 R 8 )q NHS(0) 2 Ri3; (CR 8 R 8 )q S(0) 2 NR4R 5 ; or two Ri moieties together
may form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the
alkyl, aryl, arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

R2 is a substituted aryl, heteroaryl, or heterocyclic ring which ring has a functional
moiety providing the ionizable hydrogen having a pKa of 10 or less;

R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic,
heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci- 10 alkyl; Ci_io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci- 10 alkoxy; azide; (CR 8 R 8 )qS(0) t R4,
(CR 8 R 8 )qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C1.4 alkyl;
aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl Q-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CR 8 R 8 )qNR4R5; C2-10 alkenyl

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C(0)NR4R5; (CR 8 R 8 )qC(0)NR4R5; (CR 8 R 8 )q C(O)NR4Rl0; S(0)3R 8 ;
(CR 8 R 8 )qC(0)Rn; C2-10 alkenylC(0)Ri 1; (CR 8 R 8 )qC(0)ORi 1;
C2-10alkenylC(O)ORi 1; (CR 8 R 8 )qOC(0) R\ 1; (CR 8 R 8 )qNR4C(0)Ri 1 ;
(CR 8 R 8 )q NHS(0) 2 R b ; (CR 8 R 8 )q S(0) 2 NR 4 R 5 ; (CR 8 R 8 )qC(NR4)NR 4 R 5 ;
5 (CR 8 R 8 )q NR4C(NR5)R[ 1 ; or two Y moieties together may form 0-(CH2)sO- or a

5 to 6 membered unsaturated ring; and wherein the alkyi, aryl, arylalkyl, heteroaryi,
heteroaryl alkyl, heterocyclic, heterocyciicalkyl groups may be optionally
substituted;

q is 0 or an integer having a value of 1 to 10;
10 n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a C 1-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
15 oxygen, nitrogen or sulfur;

R 8 is hydrogen or C 1-4 alkyl;
RlO is Ci-10 alkyl C(0)2R8;

Rl 1 is hydrogen, optionally substituted C\ .4 alkyl, optionally substituted aryl,

optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally
20 substituted heteroarylC i-4alkyl, optionally substituted heterocyclic, or optionally

substituted heterocyclicCi-4alkyl;

Rl2 is hydrogen, Ci-10 alkyl, optionally substituted aryl or optionally substituted

arylalkyl;

Rl3 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylC i-4alkyl,
25 heterocyclic, or heterocyclicCi_4.alkyl;

Rb is NR6R7, alkyl, aryl, aryl C 1.4 alkyl, aryl C 2 _4 alkenyl, heteroaryl, heteroaryl
Ci_4 alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclic C1.4 alkyl,
heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally

substituted;

30 or a pharmaceutical^ acceptable salt thereof.

Suitably, the variable, etc. for Formula (lb) are the same as those defined for
Formula (I) above, such as for example the functional moieties on the R2 group having
an ionizable hydrogen with a pKa of 10 or less. Suitably such functional groups
35 include, but are not limited to, hydroxy, carboxylic acid, thiol, -NH-C(0)R a , -

C(0)NR6R7, substituted sulfonamides of the formula -NHS(0)2Rb, -S(0)2NHRc,
NHC(X2)NHRb, or tetrazoyl (as defined for Formula (I).

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PCT/US96/13632

10

15

20

25

Suitably for compounds of Formula (lb), a preferred ring substitution for Ri is

in the 3-position, the 4- position or is preferably di substituted in the 3,4- position. The
substituent group is suitably an electron withdrawing moiety. Preferably R i is nitro,
halogen, cyano, trifluoromethyl group, or C(0)NR4R5.

While Y may be substituted in any of the 5 ring positions, preferably the ring
with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4-
preferably being unsubstituted. If the ring is disubstituted, substituents are preferably in
the 2' or 3' position of a monocyclic ring. While both Ri and Y can both be hydrogen,

it is prefered that at least one of the rings be substituted, preferably both rings are at
least mono-substituted, i.e. n amd m are each equal to 1 or more.

Suitably for compounds of Formula (lb), Y is more preferably disubstituted
halogen, mono-substituted halogen, disubstituted alkoxy, mono-substituted alkoxy,
methylenedioxy, aryl, or alkyl, preferably in the 2'position or 2\3'-position.

Another aspect of the present invention is the novel compounds of Formula (Ic),
a subset of compounds of Formula (I) useful for treating a chemokine mediated disease.
This invention also relates to the pharmaceutical compositions comprising a compound
of Formula (Ic) and a pharmaceutically acceptable diluent or carrier. The compounds
of Formula (Ic) are represented by the strucuture:

wherein

X is oxygen or sulfur;
X i is oxygen or sulfur;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
Ci-ioalkoxy; azide; S(0) t R4; (CRgRg)q S(0)tR4; hydroxy; hydroxy substituted
Ci_4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;
heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-l0
alkenyl; (CRgRg)q NR4R5; (CRgRg)q C(0)NR4R5; C2-10 alkenyl C(0)NR4Rs;
(CR 8 R 8 )q C(O)NR4Rl0; S(0)3R8; (CRgRg)q C(0)Ri 1; C2-10 alkenyl C(0)Ri 1;
C2-10 alkenyl C(0)ORi 1; (CRgRg)q C'(0)ORi 1; (CRgRg)q OC(0)Ri i ;
(CR 8 Rg)qNR4C(0)Ri 1; (CRgRg)q C(NR4)NR4R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 1 lt

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(CRgRg)q NHS(0)2Rb; (CRgRg)q S(0) 2 NR 4 R5, or tw ° Rl moieties together may
form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
aryialkyl, heteroaryl, heterocyclic moities may be optionally substituted;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted C1-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl C\-4 alkyl, heterocyclic, heterocyclic
Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form
a 5 to 7 member ring which may optionally comprise an additional heteroatom
selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgR8)qS(0) t R4,
(CRgR8)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Ci- 4 alkyl;
aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl Ci-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC 2 -10 alkenyl; (CRgR8)qNR4R5; C2-10 alkenyl
C(0)NR4R5; (CR 8 R 8 )qC(0)NR4R5; (CR 8 R8)q C(O)NR4Rl0; S(0)3R8;
(CR 8 R 8 )qC(0)Ri 1; C2-10 alkenylC(0)R 1 1 ; (CR 8 R 8 )qC(0)ORi 1;
C2-10alkenylC(O)ORn; (CR 8 R8)qOC(0) Rn; (CR 8 R8)qNR4C(0)Ri 1;
(CR 8 Rs)q NHS(0) 2 Rb; (CR 8 R 8 )q S(0) 2 NR4R5. (CR8R8)qC(NR4)NR 4 R 5 ;
(CR8R 8 )q NR4C(NR5)Ri 1 ; or two Y moieties together may form 0-(CH2)sO- or a

5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, aryialkyl, heteroaryl,
heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally
substituted;

q is 0 or an integer having a value of 1 to 10;

n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;

R8 is hydrogen or Ci-4 alkyl;

RlO is Ci-10 alkyl C(0) 2 R8;

Rl 1 is hydrogen, optionally substituted Ci-4 alkyl. optionally substituted aryl,

optionally substituted aryl Ci- 4 alkyl, optionally substituted heteroaryl, optionally

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WO 97/29743 PCT/US96/13632

substituted heteroarylC i -4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicCi-4alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted
arylalkyl;

5 R13 is suitably Q-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl. heteroarylC i-4alkyl,
heterocyclic, or heterocyclicCi-4alkyl;
R b is NR 6 R 7 , alkyl, aryl, aryl Ci_ 4 alkyl, aryl C2.4 alkenyl, heteroaryl, heteroaryl
Ci_4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C 1.4 alkyl,
heterocyclic C2-4 alkenyl, or camphor, all of which groups may be optionally
10 substituted; provided that

when n =1 than Y is substituted in the 2- or 3- position;

when n =2 than Y is di-substituted in the 2'- 3'- position, the 2'-5'- position, the

2'-6' position, the 3'-5' or the 3-6' position;
when n = 3 than Y is trisubstituted in the 2'-3'-5' or the 2'-3'-6'- positions;
15 further provided that

when Xi is O, m=2, R\ is 2-t-butyl, 4-methyl, and n=3 than Y is not 2'-OH,3-t-

butyl, 5'-methyl;

when Xi is O, m=l, Ri is 4-methyl, and n=2 than Y is not 2'-OH, 5'-methyl;
when Xi is O, m=l, Ri is hydrogen, and n=2 than Y is not 2'-6'-diethyl;
20 when X 1 is O, m=l, R\ is 6-OH, and n=2 than Y is not 2'-5'-methyl;

when Xi is S, m=i, Rj is 4-ethyl, and n=l than Y is not 2-methoxy;
or a pharmaceutically acceptably salt thereof.

Suitably, the variables, etc. for Formula (Ic) are the same as those defined for
25 Formula (I) above unless indicated. .

Suitably for compounds of Formula (Ic), a preferred ring substitution for Ri is
in the 3-position, the 4- position or di substituted in the 3,4- position. Preferably Ri is
other than hydrogen. The substituent group is suitably an electron withdrawing moiety.
Preferably Ri is nitro, halogen, cyano, trifluoromethyl group, or C(0)NR4Rs.

30

While Y may be substituted in any of the 5 ring positions, preferably the ring
with the Y moiety is mono-substituted in the 2-position or 3- position, with the 4-
preferably being unsubstituted. If the ring is disubstituted, substituents are preferably in
the 2' or 3' position of a monocyclic ring. While both R\ and Y can both be hydrogen,
35 it is prefered that at least one of the rings be substituted, preferably both rings are at
least mono-substituted, i.e. n amd m are each equal to 1 or more.

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WO 97/29743

PCT/US96/13632

Suitably for compounds of Formula (Ic), Y is more preferably a mono-
substituted halogen, disubstituted halogen, mono- substituted alkoxy, disubstituted
alkoxy, methylenedioxy, aryl, or alkyl, preferably with these groups in the 2'position
2,3-position.

Exemplified compounds of Formula (Ic) are:

N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenylurea;

N-[2-Hydroxy-5-nitro-phenyl]-N'-phenyl urea

N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea

N-[2-Hydroxy-4-(trifluoromethyl)phenyl]-N'-phenyl urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-hydroxy-4-nitrophenyl) urea

N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-thiourea

N-(2-Hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-trifluoromethylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea

N-{2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitrophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluorophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethoxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl) N'-(2-methylthiophenyl) urea
N-(2-Hydroxy-4-nitro-phenyl) N'-(2-chloro 6-methyl phenyl) urea
N-(2-Hydroxy-4-nitro-phenyl) N'-(2-sulfoxymethyl phenyl) urea
N-(2-Hydroxy-4-trifluoromethyl phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-trifluoromethyl phenyl)-N'-(2-phenyl phenyl) urea
N-(2-Hydroxy-4-carbomethoxy phenyl)-N'-(2-phenyl phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-dichloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,4-dichloro phenyl) urea

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N-(2-Hydroxy-4-nitrophenyl)-N'-(2-chloro phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,4-dibromo phenyl) urea
N-{2-Hydroxy-l-napthyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea
N-(2-Hydroxy-4-nitrophenyl) N'-(3-chloro 2-methoxy phenyl) urea
N-[2-Hydroxy-4-(Benzylamino)carbonyl phenyl]-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenoxy phenyl) urea
N-(2-Hydroxy-4-fluoro phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-3,4-difluoro phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-methyl phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy-4-nitro phenyl)-N'-(2-phenylamino phenyl) urea
N-(2-Hydroxy 3-carboxyphenyl)-N'-(2-bromo phenyl) urea
N-(2-Sulfhydryl-4-bromo phenyl)-N'-(2-bromo phenyl) urea
N-(2-Hydroxy 4-nitro phenyl)-N'-(2-iodo phenyl) urea
N-(2-Hydroxy 4-nitro phenyl)-N'-(2-bromo phenyl) thiourea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea
N-[2-Hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea
N-[2-hydroxy-3,4-diphenyl phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl]
N-[2-Hydroxy-3-glycincarbonylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,5-dichlorophenyl]-N*-[2-bromophenyl] urea
N-[2-Hydroxy-3-nitrophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N , -[2-bromophenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-t2-bromophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl] urea

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N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-phenylaminocarbonyl phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-cyano-4-methylphenyll-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-carbophenyl phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-carbophenyl phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3-benzyloxy phenyl]-N'-[2-bromophenyl] urea

(E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
(E)-N-[3-[2-(Methoxycarbonyl)ethenyI]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N
[2-bromophenyl] urea

(E)-N-[3-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N , -[2-brornophenyl]urea-N'-
[2-bromophenyl] urea

(E)-N-[4-[2-(Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]urea-N'-

[2-bromophenyl] urea
N-[2-Hydroxy-4-benzamide phenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-4-aminocarbonyi phenyl]-N'-[2-bromophenyl] urea
N-(2-Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N , -(2-bromophenyl)urea
N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl] urea
N-t2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-5-trifiuoromethylphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[Trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyl] urea
N- [2 -Hydroxy- 3 ,4-dichlorophenyl]-N'- [4-pheny lphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea
N-(2-Hydroxy-4-azidophenyl)-N'-(2-iodophenyl)urea
N-(2-Hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-methoxyphenyl] urea

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N-[2-Hydroxy-3-cyanophenyl]-N'-[3-trifluoromethyIphenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea
N-[2-Hydroxy-3-cyanophenyl]-N'-[2,3-dichiorophenyl] urea
N-[2-Hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-4-isopropyiphenyl]-N'-[2-chloro-5-trifluoromethylphenyl]
N-f2-Hydroxy-3-phenylphenyl]-N , -[2,3-dichJorophenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[3-trifluoromethyiphenyI] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2-phenyIphenyl] urea
N-[2-Hydroxy-5-nitrophenyl]-N'-[2,3-dichlorophenyl] urea
N-[2-Hydroxy-5-ethylsulfonylphenyi]-N'-t2,3-dichlorophenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4-dimethoxyphenyl] urea
N-[2-Hydroxy-3,4-dichiorophenyi]-N'-[2-chloro-5-trifluoromethylphenyl]
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[benzyl] urea

N- [2-Hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-(phenylaminocarbonyl) phenyl]-N'-[benzoyl] urea
N-[2-Hydroxy-3-trifluoromethylphenyl]-N*-[benzoyI] urea
N-[2-Hydroxy-4-cyanophenyl]-N'-[benzoyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[2,3-dichIorophenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[benzyl] urea

N-[2-Hydroxy-5-naphthaJenesulfonic acid]-N'-[2-bromophenyl] urea;
N-[2-Hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea;
N-(2-Hydroxy 3-napthyl) N'-(2-bromo phenyl) urea;
N-(2-Hydroxy-l-napthyl)-N'-(2-bromo phenyl) urea;
N-(2-Hydroxy-4-nitrophenyl)-N'-( 1 -naphthyl)urea;
N-(2-Hydroxy-3-nitrophenyl)-N'-(2-methoxyphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(3-trifluoromethyphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(2,3dichlorophenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(4-phenylphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(2,4-dimethoxyphenyl)urea
N-(2-Hydroxy-3-nitrophenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-(2-Hydroxy-4-amidinophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3,4-dichloro phenyl) N'( phenyl) urea
N-(2-Hydroxy-4-cyano phenyl) N'( phenyl) urea

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N-(2-Hydroxyphenyl-3-carboxylic acid)N'( phenyl) urea

N-(2-Hydroxy-3-nitrophenyl)-N'-phenylurea

N-(2-Hydroxy-3-cyanophenyl ) N'(phenyl) urea

N-(2-Hydroxy-3-cyano-4-chlorophenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-3-fluorophenyl)-N'-(phenyl)urea

N-(2-Hydroxy-3,4-difluorophenyl)-N'-(phenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2,3-methylenedioxyphenyl)urea

N-[2-(2-nitrophenylthio)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-(2-hydroxy-3-trifluoromethylphenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-hydroxy-3-trifluoromethylphenyl)-N'-(2-phenylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-benzylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylthiomethyl)phenyl]urea

N-(2-Hydroxy-4-nitro phenyl)-N'-[2-(phenyloxymethyl)phenyl]urea

N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylethyl)phenyl]urea

N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(4-trifluorophenyl)phenyl]urea

N-(2-Hydroxy-3-trifloromethylphenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-acetoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(2-cyanophenylthio)phenyl]urea

N-(2-hydroxy-3-trifluoromethyiphenyl)-N'-(2-chlorophenyl)urea

N-(2-Hydroxyethyl)-N'-(2-hydroxy-4-nitrophenyl)urea

N-2-(Benzyoxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-benzylaminophenyl)urea

N-[2-(2-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-f2-(2-Methoxycarbonylbenzyloxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)i

N-[2-(2-Carboxybenzyloxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(Benzoylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(3-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(4-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(Methoxycarbonylanuno)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

N-(2-Hydroxyeth- 1 -yloxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-benzylaminophenyl)urea

N'-[2-(2-Pyridylmethoxy)phenyl]-N'-(2-Hydroxy-4-nitrophenyl)urea

N-[2-(2-Methoxycarbonylbenzyloxyphenyl]-N-(2-hydroxy-4-nitrophenyl)u

N-[2-(2-Carboxybenzyloxy)phenyl)-N'-(2-hydroxy-4-nitrophenyl)urea

N-[2-(Benzoylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea

Additionally exemplified compounds of Formula (Ic) include:

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N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(benzyloxy)phenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(2-pyridylmethyloxy)phenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(3-pyridylmethyloxy)phenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea

5 N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-trifluorosulfonylphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2-bromophenyI)urea
N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyI)-N'-(2-bromophenyl)urea

10 N-(2-Hydroxy-4-cyanophenyi-3-carboxylic acid)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-4-trifluorosulfonylphenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea

15 N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2,3-dichlorophenyl)urea

Suitable pharmaceutically acceptable salts are well known to those skilled in the
art and include basic salts of inorganic and organic acids, such as hydrochloric acid,

20 hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane

sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid,
succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid
and mandelic acid. In addition, pharmaceutically acceptable salts of compounds of
Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance,

25 if a substituent group comprises a carboxy moiety. Suitable pharmaceutically
acceptable cations are well known to those skilled in the art and include alkaline,
alkaline earth, ammonium and quaternary ammonium cations.

The following terms, as used herein, refer to:
30 • "halo" - all halogens, that is chloro, fluoro, bromo and iodo.

• "Ci.ioalkyl" or "alkyl" - both straight and branched chain radicals of 1 to 10

carbon atoms, unless the chain length is otherwise limited, including, but not limited to,
methyl, ethyl, n-propyl, wo-propyl, n-butyl, .sec-butyl, iso-butyl, rm-butyl, n-pentyl and
the like.

35 • The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to

8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the
like.

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• The term "alkenyl" is used herein at all occurrences to mean straight or
branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto,
including, but not limited to ethenyl, 1-propenyl. 2-propenyl, 2-methyl-l-propenyl, 1-
butenyl, 2-butenyl and the like.

5 • "aryl" - phenyl and naphthyl;

• "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or
"heteroaryl alkyl") - a 5-10 membered aromatic ring system in which one or more rings
contain one or more heteroatoms selected from the group consisting of N, O or S, such
as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline,

10 quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or
benzimidazole.

• "heterocyclic" (on its own or in any combination, such as "heterocyclicalkyl")
- a saturated or partially unsaturated 4-10 membered ring system in which one or more
rings contain one or more heteroatoms selected from the group consisting of N, O, or S;

15 such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine,
tetrahydropyran, or imidazolidine.

• The term "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein
to mean Ci-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic

moiety, as also defined herein, unless otherwise indicated.
20 • "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio"

refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(0)2 moiety.

• The term "wherein two Ri moieties (or two Y moieties) may together form a
5 or 6 membered unsaturated ring" is used herein to mean the formation of a napthylene
ring system- or a phenyl moiety having attached a 6 membered partially unsaturated ring

25 such as a C6 cycloalkenyl, i.e hexene, or a C5 cyloalkenyl moiety, cyclopentene.

The compounds of Formula (I), (la), (lb), (Ic), (II, (Ila ), (lib), (lie), and (HI)
may be obtained by applying synthetic procedures, some of which axe illustrated in the
Schemes below. The synthesis provided for in these Schemes is applicable for the
30 producing compounds of Formula (I), (la), (lb), (Ic), (II, (Ila ), (lib), (lie), and (III)
having a variety of different R, Ri, and Ar groups which are reacted, employing

optional substituents which are suitably protected, to achieve compatibility with the
reactions outlined herein. Subsequent deprotection, in those cases, then affords
compounds of the nature generally disclosed. Once the urea nucleus has been
35 established, further compounds of these formulas may be prepared by applying standard
techniques for functional group intercon version, well known in the art. While the

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schemes are shown with compounds only of Formula (I) this is merely for illustration
purposes only.

Scheme 1

1 2

R=NH 2 , OH, COaH, SH a)PhNCO
NHS0 2 R

5

Ortho substituted phenyl ureas shown in 2-scheme 1 may be prepared by
standard conditions involving the condensation of commercially available ortho
substituted aniline(Aldrich Chemical Co., Milwaukee, Wi) with the commercially
available optionally substituted aryl isocyanate (Aldrich Chemical Co., Milwaukee, Wi)
10 in an aprotic solvent (DMF, toluene). When the l-(RS02NH)2-(NH2)Ph is not

commercially available it can be made by treating the commercially available RSO2CI
with the cooresponding 2-phenylene diamine in the presence of an base like triethyl
amine or NaH in an aprotic solvent (like methylene chloride or DMF).

Scheme 2

15 R--OH. NH 2 , NHSOaR a > HNO a- 23 ° C b > SnC ^ EtOH

If the desired 2-substituted aniline 5-scheme 2. is not commercially available
the corresponding nitro compound can be prepared from 3-scheme 2 . under standard
nitration conditions (using HNO3 or BF4NO3) at 23 °C. The nitro compound is then
20 reduced to the corresponding aniline using SnCl2 in EtOH(or alternately H2/Pd or
LiAlH4).

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Scheme 3

PCT/US96/13632

a) NH 4 SCN, Br 2

b) NaOH EtOH

If the desired 2-amino benzenethiol 8-scheme 3 is not commercially available it

can be synthesized by reaction of the phenyl aniline with the thiocyanate anion in the

presence of an oxidant(like bromine) to produce the 2-amino benzthiazole 7-scheme 3 .

5 This thiazole can then be hydrolyzed to the desired 2-amino benzenethiol 8-scheme 3

with a strong base like NaOH in a protic solvent (i.e., EtOH).

Scheme 4

X=S, O n

a)TBSCI, imid, DMF b)i)CICXCI, NaHCQ, iiJPhNHa c)Et 3 N«HF, CH3CN
In the case where the thioisocyanate or phenyl isocyanate is not commercially
available, the thiourea or urea 1 1 -scheme 4 may be prepared from the commercially

10 available ortho substituted aniline. This compound is first protected with a protecting
group (tert-butyl dimethyl silyl or benzyl ) by conditions well known in the art(see
Greene, T Protecting Groups in Organic Synthesis . Wiley&Sons, New York, 1981).
This protected aniline is then reacted, in the presence of a base(like triethyl amine or
sodium bicarbonate), with either thiophosgene or a solution of phosgene in an aprotic

15 solvent (ie. DMF, toluene), followed by aniline to produce the protected thiourea or
urea respectively. The corresponding urea or thiourea is then deprotected, using
conditions standard in the art, to form the desired thiourea or urea 1 1 -scheme 4-

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Scheme 5

a)(PhO) 2 PON 3 ,Et 3 N b)PhXNH 2
X=OH, NHS0 2 R, SH

Alternately the urea can be formed using a Curtius rearrangement from the

corresponding aromatic or thiophene carboxylic acid 12-scheme 5 . The carboxylic acid

is submitted to standard Curtius conditions ((PhO)2PON3, Et3N or C1COCOC1

5 followed by NaN3) and the intermediate isocyanate is trapped by an appropriately

substituted aniline.

Pharmaceutically acceptable salts of compounds of Formula (I) may be obtained
in known manner, for example by treatment thereof with an appropriate amount of acid
10 or base in the presence of a suitable solvent.

Another aspect of the present invention is the novel synthesis of cyano
nitrophenol intermediates. Numerous conversions of aryl halides to aryl cyano
derivatives with copper (I) cyanide have been published. However, no examples of an
aryl ring with a hydroxy group present were mentioned. Several attempts to obtain a
cyano phenol moiety with published results failed. Using known conditions of elevated
temperatures, greater than 170°C, such as from 180 to 210° did not yield displacment of
the halogen to a cyano moiety. Standard bases, such as DMF and pyridine further
provided no desired product. Intermediates such as 2-amino-5-fluorophenol, 2-nitro-5-
fluorophenol, 2-nitro-5-methyl-6-bromophenol were tried with a change of halogens,
from fluorine to chlorine to bromine, and with use of copper (I) cyanide. The use of a
bromine derivative, such as 2-nitro-5-methyl-6-bromophenol, with dimethylformamide
and using triethylamine with a catalytic amount of dimethylamino pyridine and copper
(I) cyanide at reduced temperatures,, i.e. <100° C, preferably 60 to about 80° C for
reduced times from strandarized procedures, i.e., < 18 hours, preferably about 4 to 6
hours yielded the desired products.

Therefore one aspect of the invention is to a process for producing a cyano
phenol derivative of the formula:

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20

WO 97/29743

PCT/US96/13632

OH

N

wherein R\ is as defined for Formula (I) above, which

method comprises reacting a compound of the formula:

wherein X is halogen with copper (I) cyanide,

10

15

20

25

dimethylformamide, triethylamine and a catalytic amount of dimethylamino pyridine.
Preferably, the process is run at reduced temperatures of about 60 to about 80° C.
Preferably X is bromine.

In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra
were performed upon a VG Zab mass spectrometer using fast atom bombardment,
unless otherwise indicated. 'H-NMR (hereinafter "NMR") spectra were recorded at 250
MHz or 400MHz using a Bruker AM 250 or Am 400 spectrometer, respectively.
Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and
br indicates a broad signal. Sat. indicates a saturated solution, equiv. indicates the
proportion of a molar equivalent of reagent relative to the principal reactant.

Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh).

SYNTHETIC EXAMPLES

The invention will now be described by reference to the following examples
which are merely illustrative and are not to be construed as a limitation of the scope of
the present invention. All temperatures are given in degrees centigrade, all solvents
used herein are of the highest available purity and all reactions are run under anhydrous
conditions in an argon atmosphere unless otherwise indicated.

General Method A: Synthesis of N, N'- phenyl urea To a solution of substituted
phenyl isocyanate (1.0 equiv.) in toluene (5 miliLiters (hereinafter "mL")) the
corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at about
80°C until complete (24-48 hours (hereinafter "hrs" or "h")), then cooled to room
temperature. The purifications, yields and spectral characteristics for each individual
compound are listed below.

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General Method B: Synthesis of N, N'- phenyl urea To a solution of phenyl
isocyanate (1.0 equiv.) in dimethyl formamide (lmL) the corresponding aniline (1.0
equiv.) was added. The reaction mixture was stirred at about 80_C until complete (24-
48 hours), then the solvent was removed under vacuum. The purifications, yields and
5 spectral characteristics for each individual compound are listed below.

General Method CiSynthesis of sulfonamide The ortho substituted aniline (1 equiv ),
triethyl amine (1 equiv.) and the desired sulfonyl chloride (1 equiv.) were combined in
methylene chloride and allowed to stir at about 23 °C until complete (12-36 h). The
10 reaction mixture was partitioned between water and methylene chloride. The organic
layer was separated and dried over magnesium sulfate, filtered and concentrated in
vacuo. The purifications of each compound are listed below.

Example 1

15 Preparation of N-f2-Hvdroxv-4-(methoxvcarbonvnphenvn-N'-phenvl urea

N-[2-Hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea was prepared from
methyl-4-amino-3-hydroxybenzoate (200 mg, 1.19 mmol) and phenyl isocyanate (1.19
mmol) according to the procedure noted above in General Method A. The product was
purified by precipitation from toluene, and filtering, to afford the titled compound (309

20 mg, 90%). mp: 188.4-188.8°C; l H NMR (CD3OD/CDCI3): d 8.15 (d, 1H, J = 8.25

Hz), 7.70 (s, 1H), 7.51 (d, 1H, J = 8.25 Hz), 7.43 (d, 2H, J = 8.25 Hz), 7.30 (t, 2H, J =
8.25 Hz), 7.01 (t, 1H, J = 8.25 Hz), 3.87 (s, 3H); EI-MS m/z 286 (M+H)+; Anal.
(Ci5Hi4N204)C,H,N.

25 Example 2

Preparation of N-r5-nitro-2-hydroxyphenyll-N'-phenyl urea

The N-[5-nitro-2-hydroxyphenyl]-N'-phenyl urea was prepared from the 5-rutro
2-hydroxy aniline and phenyl isocyanate according to the procedure in General Method
A. The product was purified by precipitation from toluene and filtering to afford the

30 titled compound (100 mg, 30%). 1H NMR (CD3OD): d 9.48 (s, 1H, NH), 9.07 (d, J =

1.56 Hz, NH), 8.55 (s, 1H), 7.80 (dd, 1H, J = 6.25 Hz and J = 1.56 Hz), 7.50 (d, 2H, J =
6.25. Hz), 7.30 (t, 2H, J = 6.25 Hz), 7.01 (m, 2H). EI-MS m/z 273 (M+H)+.

Example 3

35 Preparation of 3-hydroxy-4- ( r(phenvlamino)carbonyl]aminoibenzamide a)Preparation
of 0.67 Molar (hereinafter "M") Stock Solutions of Aluminum Amide Reagents

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To a suspension of the appropriate hydrochloride (0.02 mole (hereinafter
"mol")) in dry toluene (20 mL) at about 0°C, was slowly added a solution of (2M, 10
mL) of trimethyl aluminum in toluene. After the addition was complete, the reaction
mixture was allowed to warm to room temperature and was stirred for about 1-2 hours
5 until gas evolution has ceased.

b)Preparation of 3-hydroxy-4-{ [(phenylamino)carbonyl]amino}benzamide

To a solution of the N-[2-hydroxy-4-(methoxycarbonyl)phenyl]-N'-phenyl urea
(60 miligram (hereinafter "mg"), 0.2 mmol) in toluene (2 mL) was added aluminum
amide reagent (0.9 mL, 0.67M). The reaction mixture was stirred at reflux for about 12
10 hours. The reaction mixture was cooled to room temperature and was carefully

quenched with 5% HC1. The organic layer was separated and the aqueous layer was
extracted three times with ethyl acetate. The organic extracts were combined, dried over
MgS04, filtered and concentrated under reduced pressure. Chromatography of the

resulting solid on silica gel (ethyl acetate) gave the desired amide (28 mg, 49%). mp:
15 106.8-107. 1°C; l H NMR (CD3OD/CDCI3): d 7.98 (d, 1H, J = 8.25 Hz), 7.35 (d, 2H, J
= 8.25 Hz), 7.30 (d, 2H, J = 8.25 Hz), 7.17 (t, 2H, J = 8.25 Hz), 6.91 (t, 1H, J = 8.25
Hz); EI-MS m/z 271 (M+H)+; Anal. (C14H13N3O3) C, H, N.

Example 4

20 Preparation of N-(2-hvdroxv-4-fluorophenyl)-N'-phenyl urea
a)Preparation of 2-amino-5-fluoro phenol

A mixture of 5-fluoro-2-nitrophenol (500 mg, 3.18 mmol) and tin (II) chloride
( 1 .76 g, 9.2 mmol) in ethanol (10 mL) was heated at 80°C under argon. After 30 min,
the starting material had disappeared and the solution was allowed to cool down and

25 then poured into ice. The pH was made slightly basic (pH 7-8), by addition of 5%
aqueous sodium bicarbonate, before being extracted with ethyl acetate. The organic
phase was washed with brine, dried over MgSCH and filtered. Evaporation of the
solvent gave the title compound(335 mg, 83%). *H NMR (CD3OD/CDCI3): d 6.6 (m,
1H), 6.38 (dd, 1H, J = 8.3 Hz and J = 2.8 Hz), 6.29 (m, 1H).

30 b)Preparation of N-(2-hydroxy-4-fluorophenyl)-N' -phenyl urea

N-(2-Hydroxy-4-fluorophenyl)-N'-phenyl urea was prepared from 2-amino-5-
fluoro phenol (200 mg, 1.57 mmol) and phenyl isocyanate according to the procedure in
General Method A. The product was purified by precipitation from toluene and filtering
to afford the titled compound (352 mg, 91 %). mp: 195.5- 195.7°C; l H NMR

35 (CD3OD/CDCI3): d 7.70 (m, 1H), 7.3 (d, 2H, J = 8.25 Hz), 7. 15 (t, 2H, J = 8.25 Hz),

6.89 (t, 1H, J = 8.25 Hz), 6.50 - 6.38 (m, 2H); EI-MS m/z 246 (M+H)+; Anal.
(C13H11N2O2 F)C, H, N.

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10

cample

Preparation of 2-( rCphenvlaminolcarbonyllaminolthiophenol

2-{ [(Phenylamino)carbonyl]amino}thiophenol was prepared from 2-
aminothiophenol (200 mg, 1.6 mmol) and phenyl isocyanate according to the procedure
in General Method A. The product was purified by precipitation from toluene and
filtering to afford the titled compound (330 mg, 85 %). mp: 194.5°C; l H NMR
(CD3OD/CDCI3): d 7.48 - 7.26 (m, 4H), 7.25 - 7.10 (m, 3H), 7.04 - 6.79 (m, 2H); EI-
MS m/z 244 (M+H) + ; Anal. (C13H12N2OS) C, H, N.

Example 6

Preparation of N- r2-Carboxv-4-hvdroxvphenvh-N'-phenvl urea

N-(2-Carboxy-4-hydroxyphenyl)-N'-phenyl urea was prepared from 2-amino-5-
hydroxy benzoic acid (1 g, 6.53 mmol) according to the procedure in General Method
15 B. The reaction mixture was partitioned between ethyl acetate and water. The organic
phase was washed with brine, dried over MgS04 and filtered. Removal of solvent under

reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl
acetate, 1:1 to 100% ethyl acetate) gave the titled compound (1.5 g, 84%). *HNMR
(CD3OD/CDCI3): d 8.36 (d, 1H, J = 8.25 Hz), 7.63 (m, 4H), 7.48 (t, 2H, J = 8.25 Hz),
20 7.20 (m, 1H); EI-MS m/z 272 (M+H)+; Anal. (C14H12N2O4) C, H, N.

Example 7

Preparation of N - 12 - hydroxy - 4- (trifluoromethvh phenvll - N' - phenyl urea

a) Preparation of 2-nitro-5-trifluoromethylphenol

25 2-Nitro-5-trifluoromethylphenol was prepared by adding concentrated HNO3 (6

mL) drop-wise to a,a,a-trifluoro-m-cresol (5g, 30.8 mmol) at room temperature. After
the addition was complete the reaction was quenched with saturated ammonium acetate
and extracted with EtOAc. The organic was separated, dried over sodium sulfate and
filtered. Concentration of the solution in vacuo afforded an oil which was purified by
30 column chromatography (gradient 100% hexane to 50% EtOAc/hexanes) to afford the
titled compound as an oil( 1. 7 g, 27%). 1H NMR (CDCI3): 10.6 (s, 1H, OH), 8.26(d,

1H, J = 7.8 Hz), 7.45(s, 1H, arom), 7.26(d, 1H, J= 7.8 Hz)

b) Preparation of 2-amino-5-trifluoromethylphenol

2-Amino-5-trifluoromethylphenol was prepared by treating 2-nitro-5-
35 trifluoromethylphenol (500 mg, 2.41 mmol) with a solution of SnCl2(3.5g, mmol) in

EtOH at 23 °C for 12h. The mixture was concentrated to 50 mL and adjusted to pH 7
using saturated sodium bicarbonate. The reaction mixture was partitioned between H2O

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and EtOAc. The aqueous layer was separated and extracted with EtOAc. The
combined organic extracts were dried over sodium sulfate, filtered and concentrated in
vacuo. The resulting colorless oil(370 mg, 87%) was used without further purification.
1H NMR (CDCI3): 7.6 (s, 1H), 7.39(d, IH, J = 8.5 Hz), 7.08(d, 1H, J= 8.5 Hz)
5 c)Preparation of N - [2 - hydroxy - 4- (trifluoromethyl) phenyl] - N' - phenyl urea

N - [2 - Hydroxy - 4- (trifluoromethyl) phenyl] - N' - phenyl urea was prepared
from 2-amino-5-trifluoromethylphenol (150 mg, 1.09 mmol) and phenyl
isocyanate( 1 .09 mmol) according to the procedure in General method A. The product
was purified by precipitation from methylene chloride and filtering to afford the titled
10 compound ( 230 mg, 87% ). mp: °C; 1H NMR (DMSO-d6): d 9.45 (s, 1H, NH), 8.50
(s, 1H, NH), 8.31 (d, 1H, J = 10.0 Hz), 7.45 (d, 2H, J = 10.0 Hz), 7.29 (t, 2H, J = 6.67
Hz), 7. 10 (m, 2H), 6.99 (t. 1H, J = 6.67 Hz). EI-MS m/z 296 (M+). Anal.
(Ci4HnN202F3)C H, N.

15 Example 8

Preparation of N-r2-hvdroxv-4-nitrophenvn-N'-r2 -hvdroxv-4-nitrophenvh nre?

a) Preparation of 2-(/err-butyldimethylsilyloxy)-4-nitroaniline

To a solution of 2-amino-5-nitrophenol (1 g, 6.49 mmol) and imidazole (0.88 g,
20 12.3 mmol) in DMF (15 mL), ten -butyldimefhylsilyl chloride (1 1.2 mL, 64.9 mmol)
was added. The resulting mixture was allowed to stir at 23°C for 48 hours. The reaction
mixture was partitioned between 0.1 % HC1 and ethyl acetate. The combined organic
phase was washed with brine, dried over MgS04 and filtered. Removal of solvent at

reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethyl
25 acetate; 5: 1) gave the titled compound (1.7 g, 98 %). l H NMR (CDCI3): d 7.78 (dd,

1H, J = 6.7 Hz and J = 2.7 Hz), 7.61 (d, 1H, J = 2.7 Hz), 6.7 (d, 1H, J = 8.8 Hz), 1.0 (s,
9H), 0.28 (s, 6H).

b) Preparation of N-[(2-rm-butyldimethylsilyloxy)-4-nitrophenyl]-N'-[(2-tert-
butyldimethylsiloxy)-4- nitrophenyl] urea

30 To a solution of 2-(tert-butyldimethylsilyloxy)-4-nitroaniline(200 mg, 0.75

mmol) in toluene (10 mL) triethylamine (0.13 mL, 1.64 mmol) and triphosgene (88.4
mg, 0.3 mmol) were added. The reaction mixture was stirred at 70°C for 2 hours, then
cooled to room temperature. Then more 2-(tert -butyldimethylsilyloxy)-4-nitroaniline
(200 mg, 0.75 mmol) was added. The resulting mixture was allowed to stir at 70°C for

35 48 hours then cooled to room temperature. The reaction mixture was partitioned

between water and ethyl acetate. The combined organic phase was washed with brine,
dried over MgS04 and filtered. Removal of solvent at reduced pressure and

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chromatography of the resulting oil on silica gel (hexane : ethyl acetate, 10: 1) gave the
titled compound(130 mg, 31%). l H NMR (CDCI3): d 8.36 (d, 2H, J = 8.3 Hz), 7.90
(dd, 2H, J = 8.3 Hz and J = 2.8 Hz), 7.7 1 (d, 2H, J = 2.8 Hz), 7.22 (s, 2H), 1.02 (s,
18H),0.35 (s, 12H).

5 c) Preparation of N-(2-Hydroxy-4-nitrophenyI)-N'-(2-hydroxy-4-nitrophenyl) urea

To a solution of N-[(2-tert-butyldimethylsilyloxy)-4-nitrophenyl]-N'-[(2-tert-
butyldimethylsilyloxy)-4- nitrophenyl] urea(50 mg, 0.089 mmol) in THF (2 mL),
tetrabutylammonium fluoride ( 1 M, 0.09 mL, 0.089 mmol) was added at 0°C. The
reaction mixture was stirred at 23°C. After 1 hour, the starting material had

10 disappeared. The reaction mixture was partitioned between water and ethyl acetate. The
combined organic phase was dried over MgS04 and filtered. Removal of solvent at
reduced pressure and chromatography of the resulting oil on silica gel (hexane : ethyl
acetate; 1 : 1 to 100% ethyl acetate) gave the titled compound(24 mg, 81%). *H NMR
(CD3OD/CDCI3): d 8.32 (d, 2H, J = 8.25 Hz), 7.80 (dd, 2H, J = 8.25 Hz and J = 2.06

15 Hz), 7.7 (d, 2H, J = 2.06 Hz). EI-MS m/z 334 (M+H)+ Anal. (C13H10N4O7) C, H, N.

Example 9

Preparation of N-f 2-hvdroxy-4-nitrophenyl)-N'-p henvl-thiourea

a) Preparation of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea

20 N-(2-tert-Butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea was prepared

by treating a biphasic solution of 2-tert-butyldimethysilyloxy-4-nitroaniline(80 mg,
0.308 mmol) and NaHC03 in CHCl3:H20(2.5: 1, 7mL) with thiophosgene at 0°C. The

solution was allowed to warm to 23°C and the reaction was continued overnight. The
CHCI3 layer was separated and dried over sodium sulfate. The solution was

25 concentrated in vacuo and the residue was dissolved in toluene and treated with aniline
( 100 uL) at 23 °C for 12 h. The reaction mixture was concentrated and the residue was
purified by flash chromatography ( 10% EtOAc/hexanes) to afford the titled compound
as a yellow solid (120.8 mg, 98%) mp: 144-145°C; 1 H NMR (CD3OD/CDCI3): d 8.65
(d, 1H, J = 10.0 Hz), 7.58 (d, 1H, J = 10.0 Hz), 7.47 (d, 1H, J = 1.25 Hz), 7.26 (m, 4H),

30 7.10(m, 1H).

b) Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-phenyl-thiourea

N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-thiourea was prepared by treating a
solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea (100 mg,
0.248 mmol) in CH3CN (1 mL) with Et3N*HF (lOOuL, 0.62 mmol) in acetonitrile for
35 10 minutes at 23°C. The solution was concentrated and flushed through a silica plug
with EtOAc to afford the desired compound as an orange solid (55 mg, 77%).

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mp: 144-145°C;lH NMR (CD3OD/CDCI3): d 8.65 (d, 1H, J = 10.0 Hz), 7.58 (d, 1H, J
= 10.0 Hz), 7.47 (d, 1H, J = 1.25 Hz), 7.26 (m. 4H), 7. 10 (m, 1H).

Example 10

5 Preparation of N-(4- nitro 2-fDhenvlsulfonvlamino^p henvn-N'-phftnvl m a
a) Preparation of 4-nitro 2-(phenylsulfonylamino) aniline

A solution of 4-nitro 1 ,2-phenylene diamine(1.53 g, 10.0 mmol) in DMF was
treated with phenyl sulfonyl chloride(1.76 g, 10.0 mmol) and triethyl amine(1.01 g) in
DMF for 12 h at 23 C. The reaction mixture was partitioned between saturated NH4CI

10 and methylene chloride. The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo. The resulting solid was recrystallized (EtOH) to afford desired
(0.275 g, 9%). l H NMR(DMSO) 9.5(s, 1H, br), 7.83 (dd, 1H, J=10 Hz, 2 Hz), 7.74(d,
2H, J=8 Hz), 7.76(t, 1H, J=8 Hz), 7.56(t, 2H, J=8 Hz), 7.55(d,lH, J=2Hz), 6.79 (d, 1H,
J=8Hz), 6.5(s, 2H, br)

15 b)Preparation of N-(4- nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea

N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea was prepared from
4- nitro 2-(phenylsulfonylamino) aniline(82 mg) and phenyl isocyanate(33 mg) by
method A. The reaction was cooled and then partitioned between saturated ammonium
chloride and 9: 1 methylene chloride and methanol. The organic phase was dried over

20 magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by
column chromatography (ethyl acetate/hexanes) to afford desired(30.8 mg, 26%). EI-
MS m/z4l3(M+H) +

Example 1 1

25 Preparation of N-(2-hvdroxv-5-nitrop henvn-N^f3-methoxv-2-thienvhurea
a)Preparation of 3-methoxy-2-thienylcarboxlic acid

To a solution of 3-methoxythiophene (4.81 g, 42.1 mmol) in ether (20 mL) at -
78°C, butyllithium (17 mL, 47.6 mmol) was added. The reaction mixture was stirred at
-78°C for 1 hour, then it was warmed to 0 °C for 3 hours. After to recooling -78°C

30 the reaction mixture was poured into a beaker filled with crushed dry ice ( 14.5 g) and
allowed to stand until the excess dry ice had completely sublimed. Then the reaction
mixture was poured into a mixture of ice (10 g) to which cone. HC1 (24 mL) had been
added. The product was purified by precipitation from ether and filtering (6.42 g, 96
%). EI-MS m/z 159 (M+H) + .

35 b)Preparation of N-(2-hydroxy-5-nitrophenyl)-N'-(3-methoxy-2-thienyl)urea

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To a solution of 3-methoxy-2-thiophene carboxylic acid (200 mg, 1.27 mmol) in
benzene, (PhO)2PON3 (0.33 mL), 2-amino-4-nitrophenol (195.7 mg, 1.27 mmol) and

triethylamine (1.1 equiv., 0.25 mL) were added. The reaction mixture was stirred at
reflux overnight. The reaction mixture was partitioned between 5% citric acid and ethyl
5 acetate. The organic layer was separated and the aqueous layer was extracted three
times with ethyl acetate. The organic extracts were combined, dried over MgS04,

filtered and concentrated under reduced pressure. Chromatography of the resulting
solid on silica gel (hexane:ethyl acetate; 1: 1) gave a solid product (160 mg, 41%). mp:
172.6-173.0°C; lH NMR (CD3OD/CDCI3): d 8.96 (d, 1H, J = 2.5 Hz), 7.74 (dd, 1H, J
10 =5.0 Hz and J = 1.25 Hz), 6.82 (d, 1H, J =7.5 Hz), 6.76 (s, 2H), 3.80 (s, 3H); EI-MS
m/z 309 (M+H)+; Anal. (C12H1 1N3O5S) C, H, N.

Example 12

Preparation of N-(2-hydroxv-4-nitrophenvn-N'-(3-methoxv-2-thienvnurea
15 To a solution of 3-methoxy-2-thiophene carboxylic acid (example 11a, 200 mg,

1.27 mmol) in toluene, (PhO)2PON3 (0.33 mL) and triethylamine (1.1 equiv., 0.25 mL)
were added. The reaction mixture was stirred at 70°C for 2 hours and cooled down to
room temperature then 2-arnino-5-nitrophenol was added. The reaction mixture was
stirred at 70°C overnight. The reaction mixture was partitioned between 5% citric acid
20 and ethyl acetate. The organic layer was separated and the aqueous layer was extracted
three times with ethyl acetate. The organic extracts were combined, dried over MgS04,
filtered and concentrated under reduced pressure. Chromatography of the resulting
solid on silica gel (hexanerethyl acetate;l: 1) gave the product (190 mg, 48%). l H NMR
(CD3OD/CDCI3): d 8.38 (d, 1H, J = 5.0 Hz), 7.85 (dd, 1H, J = 5.0 Hz and J = 1.25 Hz),

25 7.76 (d, 1H, J = 2.5 Hz), 6.9 (s, 2H), 3.95 (s, 3H); EI-MS m/z 309 (M+H)+; Anal.
(Cl2HnN30 5 S)C,H,N.

Example 13

Preparation of N-r2-hvdroxv-4-nitrop henvlVN'-f3-methoxvphenvnurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-
30 hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-methoxy phenyl isocyanate( 1 .0
mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound ( 140 mg, 46%). EI-MS m/z 302(M-H) -

35 Example 14

Preparation of N-(2-hvdroxv-4-nitrophenvlVNW2-methoxvphenvnurea

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N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-methoxy phenyl isocyanate(l
mmol.) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound (82 mg, 27%). EI-MS m/z 302(M-H)-

Example 15

Preparation of N-(2-hvd roxv-4-nitrophenvn- N'-(3-trifluoromethvlphenvnurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-methoxyphenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 3-trifluoromethyl phenyl isocyanate (1
mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound (180 mg, 52%). EI-MS m/z 342(M+H) +

Example 16

Preparation of N-(2-hvdroxv-4-nitrophenvn-N'-r2-trifluoromethvlph envnurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethylphenyl)urea was prepared
from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-trifluoromethyl phenyl
isocyanate (1.0 mmol) according to the procedure in General Method B. The product
was purified by dilution with methylene chloride and precipitation with hexanes.
Filtering afforded the title compound (180 mg, 52%). EI-MS m/z 342(M+H) +

Example 17

Preparation of N-r2-hvdroxv-4-nitrophenvn-N'-( , 4-trifluoromethvlphenvnurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(4-trifluoromethylphenyl)urea was prepared
from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 4-trifluoromethyl phenyl
isocyanate (1.0 mmol) according to the procedure in General Method B. The product
was purified by dilution with methylene chloride and precipitation with hexanes.
Filtering afforded the title compound (1 1 1 mg, 32%). EI-MS m/z 340(M-H)~

Example 18

Preparation of N-(2-hvdroxv-4-nitrophenvn-N'-C2-bromophenvl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24
mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound(530 mg, 47%). EI-MS m/z 350(M-H) "

Example 19
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Preparation of N-(2-hydroxv-4-nitrnphenvl)-NV3-brornophenvl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-bromo phenyDurea was prepared from 2-
hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 3-bromo phenyl isocyanate (3.24
mmol)according to the procedure in General Method B. The product was purified by
5 dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound(0.96g, 87%). EI-MS m/z 350(M-H) "

Example 20

Preparation of N-(2-hvdroxv-4-nitrop henvn-NW4-bromophenvl)v re?
10 N-(2-Hydroxy-4-nitrophenyl)-N'-(4-bromo phenyDurea was prepared from 2-

hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 4-bromo phenyl isocyanate (3.24
mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound(0.41 g, 37%). EI-MS m/z 352(M+H) +

15

Example 21

Preparation of N-r2-hvdroxv-4-nitrophenv h-NW2-prienvIphenvnurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-phenyl phenyl isocyanate (3.24
20 mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound(0.22 g, 19%). EI-MS m/z 350(M+H) +

Example 22

25 Preparation of N-r2-hvd roxv-4-nitrophenvn-N'-( 1-naphthvHurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(l-naphthyl)urea was prepared from 2-hydroxy
4-nitro aniline (500 mg, 3.24 mmol) and 1-naphthyl isocyanate (3.24 mmol) according
to the procedure in General Method B. The product precipitated from methylene
chloride and filtered. The resulting solid was titruated with 1:3 triethyl

30 amine: methylene chloride. The filterate was concentrated in vacuo. The resulting
residue was dissolved in methylene chloride and treated with IN HC1 in water. The
desired product precipitated from solution and was collected by filtration(0. 1 lg, 10%).
EI-MS m/z 324(M+H) +

35 Example 23

Preparation of N-f2-hvdroxv-4-nitrophenvlVN'- q-nitrophenvnurea

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N-(2-Hydroxy-4-nitrophenyl)-N'-(2-nitro phenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-nitro phenyl isocyanate (3.24
mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
5 title compound(0.44 g, 44%). EI-MS m/z 3 19(M+H) +

Example 24

Preparation of N-(2-hydroxv-4-nitrophenvl)-N'-(2-fluorophenvl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluorophenyl)urea was prepared from 2-
10 hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-fluoro phenyl isocyanate (3.24
mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound(0.59 g, 31%). EI-MS m/z 292(M+H) +

Example 25

15 Preparation of N-f2-hvdroxv-4-nitr ophenvn-N'-f2.6-difluorophenvl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-difluorophenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2,6-difluoro phenyl isocyanate(3.24
mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
20 title compound(0.91 g, 91%). EI-MS m/z 308(M-H) -

Example 26

Preparation of N-f2-hvdroxv -4-nitrophenvn-N'-f2-ethoxvphenvl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethoxyphenyl)urea was prepared from 2-
hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethoxy phenyl isocyanate (3.24
25 mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound(0.84 g, 81%). EI-MS m/z 318(M+H) +

Example 27

Preparation of N-Q-hvdroxv-4-nitrophenvl)-N'-(2-ethvlDhenvl)urea
30 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-ethylphenyl)urea was prepared from 2-

hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-ethyl phenyl isocyanate (3.24
mmol) according to the procedure in General Method B. The product was purified by
dilution with methylene chloride and precipitation with hexanes. Filtering afforded the
title compound(0.44 g, 43%). EI-MS m/z 302(M+H) +

Example 28

Preparation of N-f2-hvriroxv-4-nitro phenvl)-N '-f2-trifluoromethoxvphenvnurea

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N-(2-Hydroxy-4-nitrophenyl)-N'-(2-trifluoromethyloxyphenyl)urea was
prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxy
phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The
product was purified by dilution with methylene chloride and precipitation with
5 hexanes. Filtering afforded the title compound(0.69 g, 60%). EI-MS m/z 358(M+H) +

Example 29

Synthesis of N-(2-hvdroxy-4-nitro phenyl) N'-(2-methylthio phenyl*) urea

The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg , 3.24 mmol)
10 and 2-methylthio phenyl isocyanate(3.24 mmol) by general Method B. The product
was purified by dilution with methylene chloride and precipitation with hexanes.
Filtering afforded the title compound(0.63 g, 61%). EI-MS m/z 320(M+H) +

Example 30

15 Synthesis of N-(2-hvdr oxv-4-nitro phenyl) N'-(2-chloro 6-methvl phenvH urea

The urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and
2-chloro 6-methyl phenyl isocyanate by general Method B. It was purified by dilution
with methylene chloride and precipitation with hexane. Filtering afforded the desired
compound(0.31 g, 29%). EI-MS m/z 322(M+H) +

20

Example 31

Synthesis of N-( 2-hvdroxv-4-nitro phenyl) N'-(2- methvl sulfoxvphenvl) urea

The urea was synthesized by treatment of N-( 2-hydroxy 4-nitro phenyl) N'-(2-
methyl thio phenyl) urea(example 28, 100 mg) with sodium periodate(100 mg) in t-
25 butanol/water for 12 hours at 23 °C. The product precipitated from the reaction
mixture(30 mg, 29%). EI-MS m/z 336(M+H) +

Example 32

Synthesis of N-(2-hvdroxv 4-triflu oromethvl phenyl) N'-f2-bromo phenyl) urea The
30 urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a, 0. 17 lg, 1
mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified
by dilution with methylene chloride and precipitation with hexane. Filtering afforded
the desired compound(0.25 g, 54%). EI-MS m/z 375(M+H) +

35 Example 33

Synthesis of N-r2-hvdroxv 4-carbomethoxv phen yl) N'-f2-bromo phenvH urea

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The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0.167 g, 1
mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified
by dilution with methylene chloride and precipitation with hexane. Filtering afforded
the desired compound(0.12 g, 33%). EI-MS m/z 363(M-H) "

5

Example 34

Synthesis of N-C2-hvdroxy 4-trifluoromethvl phenyl) N'-("2-phenyl phenyl) urea

The urea was prepared from 2-hydroxy 4-trifluoromethyl aniline(example 7a,
0.171 g, 1 mmol)) and 2-phenyl phenyl isocyanate by general Method B. It was
10 purified by dilution with methylene chloride and precipitation with hexane. Filtering
afforded the desired compound(0.24 g, 64%). EI-MS m/z 373(M+H) +

Example 35

Synthesis of N-(2-hvdroxy 4-carbomethoxy phenyl) N'-f 2-phenyl phenyl) urea
15 The urea was prepared from 2-hydroxy 4-carbomethoxy aniline(0. 167 g, 1

mmol) and 2-phenyl phenyl isocyanate(l mmol) by general Method B. It was purified
by dilution with methylene chloride and precipitation with hexane. Filtering afforded

the desired compound(0.185 g, 50%). EI-MS m/z 363(M-H) "

20 Example 36

Synthesis of N-f 2-hvdroxv 4-nitro phenyl) N'-(2.3-dichloro phenyl - ) urea The urea was
prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2,3-dichloro phenyl
isocyanate(2 mmol) by general Method B. It was purified by dilution with methylene
chloride and precipitation with hexane. Filtering afforded the title compound(0.5 g,

25 73%). EI-MS m/z 342(M+H) +

Example 37

Synthesis of N-t^-hvdro xv 4-nitro phenyl) N'-f2.4-dichloro phenyl) urea

The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and
30 2,4-dichloro phenyl isocyanate(2 mmol) by general Method B. It was purified by

dilution with methylene chloride and precipitation with hexane. Filtering afforded the

title compound(0.26 g, 38%). EI-MS m/z 342 (M+H) +

Example 38

35 Synthesis of N-(2-hvdroxv-4-nitro nhenvl) N'-f2 -chloro phenyl) urea

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The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and 2-
chloro phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution
with methylene chloride and precipitation with hexane. Filtering afforded the title
compound(0.29 g, 47%). EI-MS m/z 308(M+H) +

5

Example 39

Synthesis of N-(2-hvdroxv-4-nitrophe nvn N'-r2.4-dibromo phenyl*) urea

The urea was prepared from 4-nitro 2-hydroxy aniline(308 mg, 2 mmol) and
2,4-dibromo phenyl isocyanate(2 mmol) by general Method B. It was purified by
10 dilution with methylene chloride and precipitation with hexane. Filtering afforded the
title compound(0.34 g, 39%). EI-MS m/z 430(M+H) +

Example 40

Synthesis of N-(2-hydroxvnapthvl) N'-(2-bromo phenyl! urea
15 The urea was prepared from 1-amino 2-hydroxy napthalene(195 mg, 1 mmol)

and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified by
dilution with methylene chloride and precipitation with hexane. Filtering afforded the
title compound(0.030 g, 8%). EI-MS m/z 357(M+H) +

20 Example 41

Synthesis of N-(2-hvdrox v-4-nitrophenvn-N'-f2.3-methylenedioxyphenynurea

a) Preparation of 2,3-methylenedioxyphenylcarboxylic acid

A solution of 1 ,3-benzodioxole (3.09 g, 32 mmol) in dry ether (50 mL) was
25 treated dropwise at -10°C with 2.5 M n-butyllithium (15 mL, 35 mmol) in hexane.
When the addition was complete, the mixture was stirred under reflux for one hour.
After cooling to room temperature, it was added to crushed solid carbon dioxide, and
after 24 hours, the residue was treated with 10 % aq. NaHCC>3 and ether. The alkali

layer was separated, washed with ether, then acidified with cold concentrated HC1, and
30 extracted with chloroform. The combined organic layers were dried over MgS04,

filtered and concentrated under reduced pressure (1.1 g, 20 %). EI-MS m/z 167 (M+H)" 1

b) Preparation of N-(2-hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea

To a solution of the 2,3-methylenedioxyphenylcarboxylic acid in toluene,
triethylamine (0.27 mL, 1.95 mmol) and diphenylphosphoryl azide (DPPA) (0.32 mL,
35 1.5 mmol) were added. The reaction mixture was stirred at 60°C for 2 hours, then 2-
amino-5-nitrophenol (250 mg, 1.5 mmol) was added. The reaction mixture was stirred

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at 100°C for 18 hours. After the reaction mixture was cooled to room temperature, it
was partitioned between 5 % citric acid and ethyl acetate. The organic layer was
separated and the aqueous layer was extracted three times with ethyl acetate. The
organic extracts were combined, dried over MgS04, filtered and concentrated under

5 reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl
acetate; 5: 1) gave product (200 mg, 42 %). EI-MS m/z 318 (M+H) +

Example 42

Synthesis of N-(2-hvdroxv 4-nitro phenyl) N'-(2-methoxv 3-chloro phenyl) urea
10 The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2-

chloro 3-methoxy phenyl isocyanate(2 mmol) by general Method B. It was purified by
dilution with methylene chloride and precipitation with hexane. Filtering afforded the

title compound(0.48 g, 63%). EI-MS m/z 338(M+H) +
15 Example 43

Synthesis of N-C2-hvdroxv 4-nitro phen yl) N'-(2-methvl phenyl) urea

The urea was prepared from 2-hydroxy 4-nitro aniline(308 mg, 2 mmol) and 2-
methyl phenyl isocyanate(2 mmol) by general Method B. It was purified by dilution
with methylene chloride and precipitation with hexane. Filtering afforded the title

20 compound(0.38 g, 53%). EI-MS m/z 288(M+H) +

Example 44

Synthesis of NCbis r2-hvdroxv 4-nitro phenyl) N'-(dianisdine) diurea

The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg, 4 mmol) and
25 dianidisdine diisocyanate(2 mmol) by general Method B(except 2 equiv. of 4-nitro 2-
hydroxy aniline was used instead of lequiv.). The product was purified by dilution
with methylene chloride and precipitation with hexane. Filtering afforded the title

compound( 0.08 g, 6%).EI-MS m/z 605(M+H) +
30 Example 45

Synthesis of 4-methvlene bis(N-r2-chloro p henyl) N'-a-hvdroxv 4-nitro phenyl) urea)

The urea was prepared from 2-hydroxy 4-nitro aniline(616 mg, 4 mmol) and 4-
methylene bis(N-(2-chloro phenyl) diisocyanate(2 mmol) by general Method B(except 2
equiv. of 4-nitro 2-hydroxy aniline was used instead of lequiv.). The product was
35 purified by dilution with methylene chloride and precipitation with hexane. Filtering

afforded the title compound(0.10 g, 8%). EI-MS m/z 627(M+H) +

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Example 46

Synthesis of N-r2-hvdroxv 4-(benzylaminok:arbonvl phenvn-N'-(2-bromophenyDurea

5 a)Synthesis of N-(2-hydroxy 4-carboxylate phenyl) N'-(2-bromo phenyl) urea

The urea was prepared from 3-hydroxy 4-amino benzoic acid (3.69 g, 24 mmol)
and 2-bromo phenyl isocyanate(24 mmol) by general Method B. It was purified by
dilution of the DMF solution with methylene chloride and precipitation with hexane(4.0

g, 48%). EI-MS m/z 351(M+H) +

10 b)Preparation of N-[4-(benzylarrrino)carbonyl-2-hydroxyphenyl]-N'-(2-

bromophenyl)urea To a solution of the N-(2-hydroxy 4-carboxylate phenyl) N'-(2-
bromo phenyl) urea (200 mg, 0.58 mmol) in DMF (15 mL), EDC (121.9 mg, 0.58
mmol), HOBT (156.6 mg, 1 1.6 mmol) were added . The reaction mixture was stirred at
room temperature for 16 hours. Then the benzyl amine (123 mg, 1 1.6 mmol) was

15 added. The reaction mixture was stirred at same temperature for 24 hours. Then the

reaction mixture was partitioned between water and ethyl acetate. The organic layer was
separated and the aqueous layer was extracted three times with ethyl acetate. The
organic extracts were combined, dried over MgS04, filtered and concentrated under

reduced pressure. Chromatography of the resulting solid on silica gel (hexane : ethyl
20 acetate; 1:1) gave benzylamino product (500 mg, 65 %). EI-MS m/z 441 (M+H) +

Example 47

Synthesis of N-(2-hvdroxy 4-nitro phenyl) N'-(2-phenoxy phenyl) urea The urea was
synthesized by the treatment of 2-phenoxyphenyl carboxylic acid(2 mmol,) with
25 diphenyl phosphoryl azide(0.475 mL) and triethyl amine(.14 mL) in DMF at 80 °C after
24 hours the 2-amino 5-nitro phenol (1 equiv.) was added. The reaction was heated for
24 hours at 80°C. The reaction product was oiled out with hexane. The residue was
dissolved in methanol and the solid was precipitated out with water.(180 mg, 24%) EI-
MS m/z 364(M-H) "

30

Example 48

Synthesis of N-f2-hvdroxv-4-fluoro phenvH N'-(2-bromo phenvlt urea
a)Synthesis of 2-hydroxy 4-fluoro aniline

3-fluoro 6-nitro phenol (2 g, 11 mmol) was treated with 10%Pd/C(l g) at 23 °C.
35 The reaction mixture was flushed with hydrogen gas and the reaction was allowed to

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stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo to

afford the title compound (1.4 g, 77%). EI-MS m/z 169(M+H) +
b)Synthesis of N-(2-hydroxy-4-fluoro phenyl) N'-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 4-fluoro aniline(254 mg, 2 mmol) and
5 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with
methylene chloride and precipitation with hexane(173 mg, 26%). EI-MS m/z 325

(M+H) +

Example 49

10 Synthesis of N-f 2-hvdroxv 3.4-difluoro phenyl) N'-f2-bromo phenyl) urea

a) Synthesis of 2-hydroxy 3,4-difluoro aniline

2,3 difluoro 6-nitro phenol (2 g, 11 mmol) was treated with 10%Pd/C(l g) at 23
°C. The reaction mixture was flushed with hydrogen gas and the reaction was allowed
to stir 12 h before it was filtered through celite. The filtrate was concentrated in vacuo

1 5 to afforded the title compound ( 1 .6 g, 97%). EI-MS m/z 146(M+H) +

b) Synthesis of N-(2-hydroxy 3,4-difluoro phenyl) N'-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 3,4-difluoro aniline(0.290 g, 2 mmol)
and 2-bromo phenyl isocyanate(0.4 g) by general Method B. It was purified by dilution
with methylene chloride and precipitation with hexane(0.254 g, 37%). EI-MS m/z

20 343(M+H) +

Example 5Q

Synthesis of N-f2-hvdroxv 3 -napthvl) N'-(2-bromo phenvH urea

The urea was prepared from 3-amino 2-hydroxy napthalene(0.320 g, 2 mmol)
25 and 2-bromo phenyl isocyanate(.40 g) by general Method B. It was purified by dilution
of the with methylene chloride and precipitation with hexane(0.339, 47%).EI-MS m/z

357(M+H) +

Example 5}

30 Synthesis of N-f 2-hvdroxv 4-phenvl phenyl) N'-f 2-bromo phenyl) urea
a)Synthesis of 2-nitro 5-phenyl phenol

A solution of 3-phenyl phenol(2 g, 1 1 mmol) in acetic acid was treated with
concentrated nitric acid drop-wise until all starting material was consumed. The
solution was partitioned between water and methylene chloride. The organic phase was
35 separated and the aqueous phase was extracted once more with methylene chloride. The
combined organic phases were dried over sodium sulfate, filtered and concentrated in

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vacuo. The residue was purified by silica gel chromatography(ethyl acetate/hexanes) to
afford desired (1.2 g, 50%). *H NMR (CDCI3): d 10.65(s, 1H). 8.18 (d, 1H, J = 10.0
Hz), 7.65 (d, 2H, J = 6.0 Hz), 7.49 (m, 3H), 7.34 (s, 1H), 7.10 (d, 1H. J=10.0Hz).

b) Synthesis of 2-amino 5-phenyl phenol

A solution of 2-nitro 5-phenyl phenol(1.2 g, 5.5 mmol) in methanol was treated
with 10% Pd/C(1.2g). The reaction mixture was flushed with hydrogen and allowed to
stir overnight. The reaction mixture was filtered through celite and the filtrate was
concentrated in vacuo to afford desired (1.01 g, 98%).EI-MS m/z 186(M+H) +

c) Synthesis of N-(2-hydroxy 4-phenyl phenyl) N'-(2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 4-phenyl aniline(0.185 g, 1 mmol) and
2-bromo phenyl isocyanate(0.198 g) by general Method B. It was purified by dilution
of the DMF solution with methylene chloride and precipitation with hexane(215 mg,
56%).EI-MS m/z 383(M+H) +

15 Example 52

Synthesis of N-r2-hvdroxv 4-methvl p henyl) N'-C2-bromo phenyl) urea

The urea was prepared from 2-hydroxy 4-methyl aniline(.274g, 2 mmol) and 2-
bromo phenyl isocyanate(0.40 g, 2 mmol) by general Method B. It was purified by
dilution of the DMF solution with methylene chloride and precipitation with

20 hexane(249 mg, 39%). EI-MS m/z 319(M-H) "

Example 53

Synthesis of N(2-hvdroxv 4-nitro phenyl) NV2 -phenvlaminn phenyl) nrea Th,- urea was
synthesized by the treatment of 2-tertbutyldimethylsilyloxy 4-nitro phenyl
25 isocyanate(example 9a, 0.419g, 1.5 equiv.) with 2-anilino aniline(0. 1 84 g, 1 equiv.) in
THF overnight at 40 °C. The desired product precipitated out of the reaction
mixture(30 mg, 8%). EI-MS m/z 365(M+H) +

Example 54

30 Synthesis of N-(2-hvdroxv 3-carboxvlate phenyl) N'-f 2-bromo phenyls urea

The urea was prepared from 2-hydroxy 3-amino benzoic acid(300 mg, 2 mmol)
and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution of the
DMF solution with methylene chloride and precipitation with hexane(.287 g, 41%). EI-
MS m/z 351(M+H) +

Example 55
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Synthesis of N(2-sulfhv drvl 4-hromo phenyl) N'-r2-hromo phenyl) ureaa)Svnthesis of
2-amino 6-bromo thiazole

4-Bromo aniline(4.3 g, 25 mmol, 1 equiv.) and ammonium thiocyanate(5.7 g,
3equiv.) was dissolved in acetic acid and treated with bromine(4 g, lequiv.) at room
5 temperature. After complete disappearance of starting material the reaction mixture
was poured into water and the solid was collected. The solid was used in the next step

without any purification(3.6 g, 46%). EI-MS m/z 229(M+H) +

b) Synthesis of bis (3-bromo 6-amino phenyl) disulfide

The 2-amino 6-bromo thiazole hydrobromide (500 mg, 1.6 mmol) in
10 water(5mL) was treated with KOH (2.5 g) was heated at reflux for 8 h at reflux. The
reaction mixture was then acidified to ph 4 with acetic acid and extracted with
methylene chloride. The methylene chloride mixture was concentrated in vacuo. The
residue was dissolved in DMSO and treated with 12- After stirring overnight at room

temperature the reaction mixture was partitioned between methylene chloride and
15 saturated sodium bicarbonate. The methylene chloride layer was dried with magnesium
sulfate and concentrated in vacuo. The resulting solid was purified by flash
chromatography(ethyl acetate/hexane) to afford the title compound (230 mg, 34%). EI-
MS m/z 405(M+H) +

c) Synthesis of N(2-sulfhydryl 4-bromo phenyl) N'-(2-bromo phenyl) urea

20 A solution of (3-bromo 6-amino phenyl) disulfide(201 mg, .5 mmol) in DMF

was treated with 2-bromo phenyl isocyanate( 1 mmol) at 80 °C overnight. The reaction
mixture was diluted with methylene chloride and a solid was precipitated out with
hexanes. The solution was dissolved in MeOH and treated with NaBH4. After gas

evolution ceased the reaction mixture was carefully acidified with IN HC1 and the
25 resulting solid was filtered(52 mg, 13%). EI-MS m/z 399 (M-H) "

Example 56

Synthesis of N-(2-hvdroxv 4-nitro phenyl) N'-(2-iodo phe nyl) urea

The urea was synthesized by the treatment of 2-iodo benzoic acid(5 g, 20 mmol)
30 with diphenyl phosphoryl azide(l equiv.) and triethyl amine (1 equiv.) in DMF at 80
°C after gas evolution ceased the 5-nitro 2-amino phenol (3 g, 1 equiv.) was added. The
reaction was heated overnight at 80°C. The reaction mixture was purified by filtering
through a plug of silica with methylene chloride. The desired product was then
precipitated out with hexane. Filtering afforded the desired compound( 1.08 g, 13%).

35 EI-MS m/z 398(M-H)~

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Example 57

Synthesis of N-C2 -hydroxy 4-nitro phenyl) N'-(2-bromo phenyls thiourea

The thiourea was synthesized by treatment of the 2-ferf-butyldimethylsilyloxy 4-
nitro phenyl thioisocyanate(see example 9a , 3.73 mmol) with 2-bromo aniline in
5 toluene at 88°C over 36 h. The solution was concentrated and the residue was purified
by flash chromatography(EtOAc/Hexanes). The fraction slightly lower rf than starting
material contained the desired compound. This fraction was concentrated and then
treated with triethyi amine hydrofluoride in acetonitrile for 15 minutes at 23 °C. The
reaction mixture was then concentrated in vacuo and the residue was purified by flash
10 chromatography(ethyl actate/hexanes) to give N-(2-hydroxy 4-nitro phenyl) N'-(2-
bromo phenyl) thiourea(52 mg, 4%) . EI-MS m/z 369(M+H) +

Example 58

Synthesis of N-(2-phenvtsu lfamido) 4-cvanophenvl N'-f2-bromo phenyl ) urefl

15 a)Synthesis of 3-(phenylsulfamido) benzonitrile

The of 3-(phenylsulfamido) benzonitrile was synthesized from the 3-cyano
aniline (23.9 g, .2 mol) by Method C. It was purified by recrystalization from
EtOH(15.8 g, 31%).lH NMR (CDCI3): d 7.95(s, 1H), 7.84 (d, 2H, J = 8.0 Hz), 7.59 (t,
1H, J = 8.0 Hz), 7.45 (m, 2H), 7.35 (m, 4H).

20 b)Synthesis of 3-(phenylsulfamido) 4-nitro benzonitrile

The 3-(phenylsulfamido) benzonitrile(10 g, 39 mmol) was dissolved in acetic
anhydride and treated with concentrated nitric acid dropwise at room temperature until
all the starting material had been consumed. The reaction mixture was then quenched by
carefully pouring it into sodium bicarbonate and left to sit until all gas evolution had

25 subsided. It was then partitioned between methylene chloride and water. The organic
layer was dried over sodium sulfate and filtered. The reaction mixture was
concentrated in vacuo, absorbed onto silica gel and purified by column
chromatography(methylene chloride/hexane) to afford the title compound (I.7g, 15%).
EI-MS m/z 302(M+H) +

30 c)Synthesis of 3-(phenylsulfamido) 4-amino benzonitrile

The 3-(phenylsulfamido) 4-nitro benzonitrile(1.5 g, 4.9 mmol) was treated with
tin chloride dihydrate in EtOH at 80 °C for 12h. It was then concentrated and flushed
through a plug of silica gel with 5% methanol/methylene chloride. The filterate was
absorbed onto silica gel and purified by flash chromatography(ethyl acetate/hexane) to

35 afford the title compound (0.9 g, 60%). EI-MS m/z 274 (M+H) +

d)Synthesis of N-(2-phenylsulfamido) 4-cyanophenyl N'-(2-bromo phenyl) urea

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The urea was synthesized from 2-(phenylsulfamido) 4-amino benzonitrile(77
mg, 0.28 mmol) and 2-bromo phenyl isocyanate by general Method C. It was purified
by column chromatography(ethyl acetate/hexane) to afford the title compound (30 mg,

22%). EI-MS m/z 469(M-H) "

5

Example 59

Synthesis of N-(2-(phenvl sulfamido) p henyl) N'-^-bromo phenyl) urea

a) Synthesis of 2-( phenyl sulfamido) aniline

The sulfonamide was synthesized from phenyl sulfonyl chloride(0.0 1 mmol) and
10 o-phenylene diamine( 1.08 g, 0.01 mmol) by general Method C. It was purified by

recrystallization from EtOH(1.0 g, 40%).EI-MS m/z 249(M+H) +

b) Synthesis of N-(2-(phenyl sulfamido) phenyl) N' -(2-bromo phenyl) urea

The urea was synthesized 2-(phenyl sulfamido) aniline(l mmol)
and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with
15 methylene chloride and precipitation with hexane. Filtering afforded the desired

compound(0.234 g, 52%).EI-MS m/z 446(M+H) +

Example $q

Synthesis of N-f2-( r stvrvl sulfamido^ p henvh N'-f2-hromo phenyl) urea
20 a)Synthesis of 2-( styryl sulfamido) aniline

The sulfonamide was synthesized from styryl sulfonyl chloride(0.01 mol) and o-
phenylene diamine(0.01 mol) by general Method C. It was purified by recrystallization

from EtOH(1.2 g, 60%)EI-MS m/z 199(M+H) +

b)Synthesis of N-(2-(styryl sulfamido) phenyl) N'-(2-bromo phenyl) urea
25 The urea was synthesized from 2-(styryl sulfamido) anilined mmol) and 2-

bromo phenyl isocyanate(l mmol) by general Method B. It was purified by dilution
with methylene chloride and precipitation with hexane. Filtering afforded the desired

compound(0.309 g, 65%). EI-MS m/z 472(M+H) +

30 Example 61

Synthesis of 2-rf3.4 dimethoxv phenvnsulfnnvl amino! phenyl) N'-(2-bromo Phenyl)
urea

a)Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonyl amino]phenyl aniline

The sulfonamide was synthesized from 3,4-dimethoxy phenyl sulfonyl
35 chloride(0.01 mol) and o-phenylene diamine by general Method C. It was purified by

recrystallization from EtOH(0.65 g, 21%). EI-MS m/z 309(M+H) +

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b)Synthesis of 2-[(3,4-dimethoxyphenyl)sulfonyIamino] phenyl) N'-(2-bromo phenyl)
urea

The urea was synthesized from 2-[(3,4-dimethoxyphenyl)sulfonyl aminojphenyl
aniline( 1 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified
by dilution with methylene chloride and precipitation with hexane. Filtering afforded

the desired compound(0.062 g, 12%).EI-MS m/z 504(M-H) "

Example 62

Synthesis of N-(2-rf4-acetamidophenvnsulfon vlarninol phenvn N'-r2-bromo phenvn
urea

a) Synthesis of 2-[(4-acetamidophenyl)sulfonylamino]phenyl aniline

The sulfonamide was synthesized from 4-acetamidophenyl sulfonyl
chloride(0.0 1 mol) and o-phenylene diamine(0.01 mol) by general Method C. It was
purified by recrystallization from EtOH(1.27 g,40%)EI-MS m/z 304(M-H) ".

b) Synthesis of N-(2-[(4-acetaniidophenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl)
urea

The urea was synthesized from 2-[(4-acetamidophenyl)sulfonylamino]phenyl
aniline(l mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was
purified by dilution with methylene chloride and precipitation with hexane. Filtering
afforded the desired compound(0.12 g, 24%). EI-MS m/z 501(M-H) "

Example 63

Synthesis of N-f2-f2-thiophene s ulfamido phenyl 1 ) N'-f2-bromo phenvn urea

a) Synthesis of 2-(2-thiophene sulfamido) aniline

The sulfonamide was synthesized from 2-thiophene sulfonyl chloride(0.01 mol)
and o-phenylene diamine(0.01 mol) by general Method C. It was purified by

recrystallization from EtOH(0.77 g, 30%). EI-MS m/z 255 (M+H) +

b) Synthesis of N-(2-(2-thiophene sulfonyl amino phenyl) N'-(2-bromo phenyl) urea

The urea was synthesized from 2-( 2-thiophene sulfonyl amino) aniline( 1
mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified
by dilution with methylene chloride and precipitation with hexane. Filtering afforded
the desired compound(0.29 g, 64%). EI-MS m/z 450(M-H) "

Example 64

Synthesis of N-f2-(3-mlvl sulfonvl amino phenvn N'-r2-bromo phenvn urea
a)Synthesis of 2-( 3-tolyl sulfonyl amino) aniline

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The sulfonamide was synthesized from 3-tolyl sulfonyl chloride(0.01 mol) and
o-phenylene diamine(0.01 mol) by general Method C. It was purified by

recrystallization from EtOH(0.73g, 28%).EI-MS m/z 263 (M+H) +
b)Synthesis of N-(2-((3-tolyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea
5 The urea was synthesized from 2-(3-tolyl sulfonyl amino) aniline(l mmol) and

2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified by dilution
with methylene chloride and precipitation with hexanes. It was recrysallized two times

with EtOH(25 mg, 5%). EI-MS m/z 458(M-H) "

10 Example 65

Synthesis of N-(2-f8-quinolin vl sulfonvl amino) phenyl) N'-f2- bromo phenyl) urea

a) Synthesis of 2-(8-quinolinyl sulfonyl amino) aniline

The sulfonamide was synthesized from 8-quinolinyl sulfonyl chloride(0.0 1 mol)
and o-phenylene diamine(0.01 mol) by general Method C. It was purified by

15 recrystallization from EtOH(0.82 g, 27%).EI-MS m/z 300 (M+H) +

b) Synthesis of N-(2-( (8-quinolinyl) sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea

The urea was synthesized from 2-((8-quinolinyl) sulfonyl amino) aniline(l
mmol) and 2-bromo phenyl isocyanate(l mmol) by general Method B. It was purified
by dilution with methylene chloride and precipitation with hexane. Filtering afforded

20 the desired compound(0.23 g, 46%).EI-MS m/z 495(M-H) "

Example 66

Synthesis of N-f2-f henzvl su lfonvl amino) phenyl) N'-(2-bromo phenyl) urea

a) Synthesis of 2-(benzyl sulfonyl amino) aniline

25 The sulfonamide was synthesized from benzyl sulfonyl chloride(0.01 mol) and

o-phenylene diamine(0.01 mol) by general Method C. It was purified by
recrystallization from EtOH(0.87g, 33%). EI-MS m/z 263(M+H)+.

b) Synthesis of N-(2-( benzyl sulfonyl amino) phenyl) N'-(2-bromo phenyl) urea

The urea was synthesized from 2-( benzyl sulfonyl amino) aniline( 1 mmol)
30 and 2-bromo phenyl isocyanate( lmmol) by general Method B. It was purified by

dilution with methylene chloride and precipitation with hexane. Filtering afforded the
desired compound(0. 1 1 g, 23%). EI-MS m/z 460 (M+H)+

Example 67

35 Synthesis of N-(2-hvdroxv-4-azidop henvn-N'-(2-methoxvphenvl)urea
a)Synthesis of N-(2-hydroxy-4-aminophenyl)-N'-(2-methoxyphenyl)urea

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To a solution of N-(2-hydroxy-4-nitro phenyl)-N'-(2-methoxyphenyl)urea(1.0 g,
example 15) in methanol, palladium (on activated carbon, 10%) (100 mg) was added.
Then the reaction mixture was hydrogenated under a hydrogen balloon for 18 hours.
The solid was filtered off by celite and washed three times by methanol. The filtrate was
5 concentrated under reduced pressure to give amine compound (0.8 g, 89%). EI-MS m/z
274 (M+H) +

b)Synthesis of N-(2-hydroxy-4-azidophenyl)-N'-(2-methoxyphenyl)urea

The N-(2-hydroxy-4-aminophenyl)-N'-(2-methoxyphenyl)urea (300 mg, 1.17
mmol) was added to HCI/H2O (1.17 ml72.34 mL), cooled to 0°C. Sodium nitrite (80.7
10 mg, 1.17 mmol) was added to the reaction mixture. The reaction mixture was stirred at
0°C for 30 minutes. The sodium azide (76 mg, 1.17 mmol) was added to reaction
mixture and it was warmed to room temperature. The reaction mixture was stirred at
room temperature for 18 hours. Then it was extracted with three times by ethyl acetate.
The organic extracts were combined, dried over MgS04, filtered and concentrated

15 under reduced pressure and chromatography of the resulting solid on silica gel (hexane :
ethyl acetate; 5:1) gave product (125 mg, 38%). EI-MS m/z 300 (M+H) +

Example 68

Preparation of N-r2-hvdrox v-5-cvanophenvn-N'-r2-bromophenvn urea

20 a)Preparation of 2-amino-4-cyanophenol

To a solution of 2-nitro-4-cyanophenol(10g, 61mmol) in methanol(250mL) was
added 10% Pd/C (lg). The mixture was flushed with argon, then hydrogen was
bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at
balloon pressure overnight. The mixture was filtered through celite and the celite was

25 washed with methanol. The solvent was evaporated and chromatography of the

resulting solid on silica gel (5%MeOH/ CH2CI2) gave the desired product(8.0 g, 97%).

l R NMR (CD3OD): d 6.96 (d, 1H), 6.90 (dd, 1H), 6.77 (d, 1H).
b)Preparation of N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea

N-[2-hydroxy-5-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-
30 amino-4-cyanophenol(268mg, 2.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane( 1/20) and filtering. (540mg,81%). l H NMR (CD3OD): d 8.10 (d, 1H), 7.87 (d,
1H), 7.43 (d, 1H), 7.20 (t, 1H), 7.09 (d, 1H), 6.86 (t, 1H), 6.77 (d, 1H).

35 Example 69

Preparation of N-r2-hvdroxv-3-fluorophenvn-N'-r2-bromophenvn urea

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a) Preparation of 2-amino-3-fluorophenol

To a solution of 2-nitro-3-fluorophenol(lg, 6.4mmol) in methanol(250mL) was
added 10% Pd/C (lg). The mixture was flushed with argon, then hydrogen was
bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at
5 balloon pressure overnight. The mixture was filtered through celite and the celite was
washed with methanol. The solvent was evaporated and chromatography of the
resulting solid on silica gel (5%MeOH/ CH2CI2) gave the desired product(650 mg, 80.2

%). l H NMR (CD3OD): d 6.41-6.17 (m, 3H).

b) Preparation of N-[2-hydroxy-3-fluorophenyl]-N'-[2-bromophenyl] urea

10 N-[2-Hydroxy-3-fluorophenyl]-N'-[2-bromo phenyl] urea was prepared from 2-

amino-3-fluorophenol (254mg, 2.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (500 mg, 77%). ! H NMR (CD3OD): d 8.05 (d, 1H), 7.50
(d, 1H), 7.26 (t, 1H), 7.18 (d, 1H), 6.92 (t, 1H), 6.86-6.68 (m, 2H).

15

Example 70

Preparation of N-2-f l-hvdroxyfluorenel-N'-r2-bromophenvn urea

a) Preparation of 2-amino-l-hydroxyfluorene

To a solution of l-hydroxy-2-nitrofluorene(250 mg, 1.23mmol) in
20 methanol(250mL) was added 10% Pd/C (lg). The mixture was flushed with argon,

then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere
was maintained at balloon pressure overnight. The mixture was filtered through celite
and the celite was washed with methanol. The solvent was evaporated and
chromatography of the resulting solid on silica gel (5%MeOH/ CH2CI2) gave the

25 desired product(171 mg, 81.2 %). l H NMR (CD3OD): d 7.60 (d, 1H), 7.47 (d, 1H),
7.28 (t, 1H), 7.18 (m, 2H), 6.82 (d, 1H), 3.76 (s, 2H).

b) Preparation of N-2-[l-hydroxyfluorene]-N'-[2-bromophenyl] urea

N-2-[l-hydroxyfluorene]-N'-[2-bromo phenyl] urea was prepared from 2-
amino-1- hydroxyfluorene (I70mg, 0.86 mmol) according to the procedure in General
30 Method B. The product was purified by chromatography of the resulting solid on silica

gel (30%EtOAc/ Hexane) to give the desired product (300mg, 84.5%). l H NMR
(CD3CI): d 8.04 (d, 1H), 7.66 (d, 1H), 7.49 (t, 2H), 7.35-7.20 (m. 4H), 7.09 (d, 1H),

6.90 (t, 1H).

35 Example 71

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Preparation of N-3-r2-hvdroxv-9. 1 O-anthragiiinonvll-N' -Q-bromophenvll urea N-3-
[2-Hydroxy-9.10-anthraquinonyl]-N'-[2-bromophenyl] urea was prepared from 2-
hydroxy-3-aminoanthraquinone(480mg, 2.00 mmol) according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
5 hexane(l/20) and filtering. (610mg, 70%). *H NMR (CD3OD): d 8.93 (s,lH), 8.12
(m, 2H), 8.02 (d, 1H), 7.77 (m, 2H), 7.61 (d, 1H), 7.52 (s, 1H), 7.38 (t, 1H), 7.05 (t,
1H).

Example 72

10 Preparation of N-r2-hydroxy-3-fluoro-5-bromophenvll-N'-r2-bromophenvll urea
a)Preparation of 2-amino-6-fluoro-4-bromophenol

A mixture of 4-bromo-2-fluoro 6-nitxophenol(lg, 4.2mmol) and tin (II) chloride
(4.78 g, 21.2mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours,
the starting material had disappeared and the solution was allowed to cool down and

15 then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid
NaOH, before being extracted with ethyl acetate. The organic phase was washed with
brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography
of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(710

mg, 82 %). [ H NMR (CD3OD): d 6.51-6.40 (m, 2H).

20 b)Preparation of N-[2-hydroxy-3-fluoro-5-bromophenyl]-N'-[2-bromophenyl] urea

N-[2-hydroxy-3-fIuoro-5-bromophenyl]-N'-[2-bromophenyl] urea was prepared
from 2-amino-6-fluoro-4-bromophenol (254mg, 2.00 mmol) according to the procedure
in General Method B. The product was purified by precipitation from methylene
chloride/ hexane(l/20) and filtering. (500 mg, 77%). *H NMR (CD3OD): d 7.98 (s,

25 1H), 7.91 (d, 1H), 7.60 (d, 1H), 7.33 (t, 1H), 7.00 (t, 1H), 6.94 (d, 1H).

Example 73

Preparation of N-r2-hvdroxv-3-chlorophenvn-N'-r2-bromophenvl1 urea
a)Preparation of 2-amino-3-chlorophenol

30 A mixture of 3-chloro-2-nitrophenol(250 mg, 1.4mmol) and tin (II) chloride

(1.2 g, 5.3mmol) in ethanol(50mL) was heated at 80_C under argon. After 2 hours, the
starting material has disappeared and the solution was allowed to cool down and then
poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH,
before being extracted with ethyl acetate. The organic phase was washed with brine,

35 dried over MgS04 and filtered. The solvent was evaporated and chromatography of the

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resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(143 mg, 69
%). L H NMR (CD3OD): d 6.75 (t.lH), 6.70 (d, 1H), 6.65 (d, 1H).
b)Preparation of N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea

N-[2-hydroxy-3-chlorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-
5 amino-3-chlorophenol (143mg, 1.00 mmol) according to the procedure in General

Method B. The product was purified by chromatography of the resulting solid on silica

gel (30%EtOAc/ Hexane) to give the desired product(195mg, 57%). l H NMR
(CD3OD): d 7.81 (d, 1H), 7.68 (d, 1H), 7.47 (d, 1H), 7.20 (t, 1H), 6.90 (m, 2H), 6.70

(t. 1H).

10

Example 74

Preparation of N-r2-hvdroxv-3-trifluor omethvlphenvn-N'-r2-bromophenvl1
urea a)Preparation of 2-nitro-6-trifluoromethylphenol

2-trifluoromethylphenol (3.00g, 18.5mmol) was dissolved in methylene

15 chloride(40mL) followed by the addition of sodium nitrate ( 1 .73g, 20.4mmol). The
addition of sulfuric acid (23 mL/ 3M) was then made, followed by addition of a
catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the
reaction mixture was diluted with methylene chloride and extracted with water. The
organic layer was dried over MgS04 and filtered. The solvent was evaporated and

20 chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

desired product(1.84 g, 47 %). l H NMR (CD3COCD3): d 8.35 (d.lH), 7.95 (d, 1H),
7.13 (t, 1H).

b) Preparation of 2-amino-6- trifluoromethylphenol

A mixture of 6-trifluoromethyl-2-nitrophenol(1.84 g, 8.67 mmol) and tin (II)
25 chloride (6.0 g, 26.2 mmol) in ethanol( 1 50mL) was heated at 80°C under argon. After
2 hours, the starting material has disappeared and the solution was allowed to cool down
and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid
NaOH, before being extracted with ethyl acetate. The organic phase was washed with
brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography
30 of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product( 1 .35 g,
88 %). l H NMR (CD3OD): d 6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d. 1H).

c) Preparation of N-[2-hydroxy-3- trifluoromethylphenyl]-N'-[2-bromophenyl] urea

N-[2-hydroxy-3-trifluoromethylphenyl]-N'-[2-bromophenyl] urea was prepared
from 2-amino-6-trifluoromethylphenol (280mg, 1.60 mmol) according to the procedure
35 in General Method B. The product was purified by precipitation from methylene

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chloride/ hexane( 1/20) and filtering. (390mg, 65%). l H NMR (CD3OD): d 7.99 (d,
1H), 7.60 <d, 1H), 7.58 (d, 1H), 7.34 (t, 1H), 7.30 (d, 1H), 7.00 (t, 1H), 6.96 (d, 1H).

Example 75

Preparation of N-B.4 diphenvl-2 -hvdroxvphenvn-N'-r2-bromophenvM urea

N-[3,4 diphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from
2-amino-5,6 diphenylphenol (50mg, 0.19 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering (61mg, 69%). *H NMR (CD3OD): d 7.97 (d, 1H). 7.66 (d,
1H), 7.58 (d, 1H), 7.31 (t, 1H), 7.25-7.00 (m, 11H), 6.91 (d, 1H).

Example 76

Preparation of N-r2-hvdroxv-3-glvcinemethvlestercarhn nvlphenvn-N'-r2-bromophenvn
urea

N-[2-hydroxy-3-glycinemethylestercarbonylphenyl]-N , -[2-bromophenyl] urea
was prepared from 6-glycinemethylestercarbonyl-2-aminophenol (50mg, 0.22 mmol),
purchased from the University of New Hampshire, according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering (65mg, 69%). l H NMR (CD3OD): d 8.14 (d, 1H), 7.96 (d,
1H). 7.49 (d, 1H), 7.24 (t, 2H), 6.89 (dd, 1H), 6.81 (t, 1H), 4.10 (s,2H), 3.74 (s,3H).

Example 77

Preparation of N-r2-hvdroxv-3-gl vcinecarbonvlphenvn-N'-r2-bromophenvn urea N-[2-
Hydroxy-3-glycinecarbonylphenyl]-N'-[2-bromophenyl] urea was prepared from N-[2-
hydroxy-3-glycinemethylestercarbonylphenyl]-N'-[2-bromophenyl] urea(50mg, 0. 1 2
mmol) by stirring in a 3/1 ratio of methanol/water (10 mL). Addition of 1 equiv. of
lithium hydroxide was added and stirring continued until the starting material had
disappeared. (45mg, 92%). The product was purified by chromatography of the
resulting solid on silica gel (9/1/0.1 CH2CI2/ MeOH/ AcOH) to give the desired

product(195mg, 57%). l K NMR (CD3OD): d 8.14 (d, 1H), 7.92 (d, 1H), 7.60 (d, 1H),
7 46 (d, 1H), 7.34 (t, 1H), 7.04 (t, 1H), 6.82 (t, 1H), 3.96 (2H).

Example 78

Preparation of N-r2-hvdroxv-3.5-dichlorophenv n-N'-r2-bromophenvll urea
a)Preparation of 2-amino-4,6-dichlorophenol

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A mixture of 4,6-dichloro-2-nitrophenol{l g, 4.8mmol) and tin (II) chloride (3.2
g, 14.4mmol) in ethanol(50mL) was heated at 80° C under argon. After 2 hours, the
starting material had disappeared and the solution was allowed to cool down and then
poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH,
5 before being extracted with ethyl acetate. The organic phase was washed with brine,
dried over MgS04 and filtered. The solvent was evaporated and chromatography of the
resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(685 mg, 80

%). l H NMR (CD3OD): d 6.75 (s,lH), 6.61 (s, 1H).

b)Preparation of N-[2-hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea
10 N-[2-Hydroxy-3,5-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from

2-amino-4,6-dichlorophenol (143mg, 1.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane( 1/20) and filtering. (660mg, 88%). *H NMR (CD3OD): d 7.96 (s, 1H), 7.89

15

(d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.00 (t, 1H), 6.95 (dd, 1H).

Example 79

Preparation of N-r2-hvdroxv -3-nitrophenvn-N'-r2-bromophenvn ureaN-r2-Hydroxv-3-
nitrophenyl]-N'-[2-bromophenyl] urea was prepared from 2-hydroxy-3-nitroaniline
(1.25g, 8. 1 mmol) according to the procedure in General Method B. The product was
20 purified by precipitation from methylene chloride/ hexane(l/20) and filtering. (2.4g,
84%). l H NMR (CD3OD): d 8.45 (d, 1H), 7.94 (d, 1H), 7.78 (d, 1H), 7.60 (d, 1H),
7.35 (t, 1H), 7.01 (m, 2H).

Example 80

25 Preparation of N-r2-hvdroxv-4-naphthalenesulfonic acid1- N'-r2-bromophenvll urea
N-[2-hydroxy-4-naphthalenesulfonic acid]-N'-[2-bromophenyl] urea was
prepared from l-amino-2-hydroxy-4-naphthalensulfonic acid (0.48g, 2.0 mmol)
according to the procedure in General Method B and the addition of lmL of
triethylamine The product was purified by precipitation from methylene chloride/

30 hexane(l/20) and filtering. (690 mg, 79%). l H NMR (CD3OD): d 8.14 (s, 1H), 8.04
(d, 1H), 7.98 (m, 2H), 7.61-7.55 (m, 3H), 7.43 (t, 1H), 6.98 (t, 1H).

Example 81

Preparation of N-r2-hvdroxv-5- naphthalenesulfonic acidl-N'-r2-bromophenvn urea
35 N-3-[2-hydroxy-5-naphthalensulfonic acid]-N'-[2-bromophenyl] urea was

prepared from 2-amino-3-hydroxy-6-naphthalensulfonic acid (0.48g, 2.0 mmol)

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according to the procedure in General Method B and the addition of lmL of
triethylamine The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (715 mg, 82%). *H NMR (CD3OD): d 8.09 (s, 1H), 7.96
(d, 1H), 7.65-7.48 (m, 3H), 7.36 (t, 1H), 7.25 (s, 1H), 7.04 (m, 2H).

5

Example 82

Preparation of N-f2-hydroxv-3.4-dichlorophenvll-N'-r2-bromophenyn urea

a) Preparation of 2-nitro-5,6 dichlorophenol

2,3-dichlorophenol (3.26g, 20mmol) was dissolved in methylene
10 chloride(40mL) followed by the addition of sodium nitrate (1.88g, 22mmol). The

addition of sulfuric acid (20mIV 3M) was then made, followed by addition of a catalytic
amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic
layer was dried over MgS04 and filtered. The solvent was evaporated and
15 chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

desired product(1.8 g, 44 %). *H NMR (CD3COCD3): d 8.04 (d,lH), 7.15 (d, 1H).

b) Preparation of 2-amino-5,6 dichlorophenol

A mixture of 5,6-dichloro-2-nitrophenol(1.8 g, 8.7mmol) and tin (II) chloride
(5.8 g, 26. lmmol) in ethanol(50mL) was heated at 80_C under argon. After 2 hours,
20 the starting material had disappeared and the solution was allowed to cool down and
then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid
NaOH, before being extracted with ethyl acetate. The organic phase was washed with
brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography
of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(1.4

25 mg, 90 %). ! H NMR (CD3OD): d 6.71 (d, 1H), 6.45 (d, 1H).

c) Preparation of N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-bromophenyl] urea was prepared from
2-amino-5,6-dichlorophenol (350mg, 2.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
30 hexane(l/20) and filtering. (670mg, 89%). l H NMR (CD3OD): d 7.90 (d, 1H), 7.85
(d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 6.99 (t, 1H), 6.96 (d, (1H).

Example 83

Preparation of N -r2-hvdroxv-3-cvanophenvn-N'-r2-bromophenvl1 urea
35 a)Preparation of 2-nitro-6-cyanophenol

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2-cyanophenol (2.38g, 20mmol) was dissolved in methylene chloride(40mL)
followed by the addition of sodium nitrate (1.88g, 22mmol). The addition of sulfuric
acid (20mL/ 3M) was then made, followed by addition of a catalytic amount of sodium
nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was
5 diluted with methylene chloride and extracted with water. The organic layer was dried
over MgS04 and filtered. The solvent was evaporated and chromatography of the
resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(1.4 g, 42 %).

'hNMR (CD3COCD3): d 8.47 (d,lH), 8.15 (d, 1H), 7.30 (t, 1H).

b) Preparation of 2-amino-6-cyanophenol

10 A mixture of 6-cyano-2-nitrophenol(600 mg, l.Ommol) and tin (II) chloride (3.2

g, 14.4mmol) in acetic acid(50mL) was heated at 80_C under argon. After 2 hours, the
starting material has disappeared and the solution was allowed to cool down and then
poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH,
before being extracted with ethyl acetate. The organic phase was washed with brine,

15 dried over MgS04 and filtered. The solvent was evaporated and chromatography of the
resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(365 mg, 75
%). l H NMR (CD3OD): d 6.92 (d, 1H), 6.85-6.69 (m,2H).

c) Preparation of N-[2-hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-3-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-
20 amino-6-cyanophenol (134mg, 1.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (260mg, 78%). l H NMR (CD3OD): d 7.98 (d, 1H), 7.74
(d, 1H), 7.57 (d, 1H), 7.30 (t, 1H), 7.22 (d, 1H), 6.98 (t, 1H), 6.94 (t, (1H).

25 Example 84

Preparation of N-f2.hvdroxv-4 -cvanophenvll-N'-r2-bromophenvn urea

a) Preparation of 2-nitro-5-cyanophenol

3-cyanophenol (2.38g, 20mmol) was dissolved in methylene chloride(40mL)
followed by the addition of sodium nitrate ( 1.88g, 22mmol). The addition of sulfuric

30 acid (20ml7 3M) was then made, followed by addition of a catalytic amount of sodium
nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was
diluted with methylene chloride and extracted with water. The organic layer was dried
over MgS04 and filtered. The solvent was evaporated and chromatography of the
resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(910 mg, 28

35 %). l H NMR (CD3COCD3): d 8.30 (d,lH), 7.67 (s,lH), 7.49 (d, 1H).

b) Preparation of 2-amino-5-cyanophenol

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A mixture of 5-cyano-2-nitrophenol(250 mg, 1.5mmol) and tin (II) chloride (3.2
g, 14.4mmol) in ethanol(50mL) was heated at 80_C under argon. After 2 hours, the
starting material has disappeared and the solution was allowed to cool down and then
poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH,
before being extracted with ethyl acetate. The organic phase was washed with brine,
dried over MgSC>4 and filtered. The solvent was evaporated and chromatography of the
resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(175 mg, 86
%). l H NMR (CD3OD): d 7.00 (d, 1H), 6.88 (s.lH), 6.69 (d, 1H).
c)Preparation of N-[2-hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-bromophenyl] urea was prepared from 2-
amino-5-cyanophenol (170mg, 1.27 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering (310mg, 74%). *H NMR (CD3OD): d 8.25 (d, 1H), 7.91 (d,
1H), 7.59 (d, 1H), 7.33 (t, 1H), 7.17 (d, 1H). 7.07 (s, 1H). 7.01 (t, (1H).

Example 85

Preparation of N-r2-hvdroxv-4-cvanophenvn-N'- r4-methoxvphenvn urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[4-methoxyphenyl] urea was prepared from
2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (1 10mg,86%). l H NMR (CD3OD): d 8.23 (d, 1H), 7.61-
7.51 (m, 2H), 7.32 (d, 1H), 7.20 (d, 1H), 7.15 (d, 1H), 7.03 (s, 1H).

Example 86

Preparation of N-r2-h vdroxv-4-cvanophenvn-N'-f2-phenvlphenvn urea N-[2-
Hydroxy-4-cyanophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-5-
cyanophenol (170 mg, 1.27 mmol) according to the procedure in General Method B.
The product was purified by precipitation from methylene chloride/ hexane( 1/20) and
filtering. (150mg, 85%). l H NMR (CD3OD): d 8.20 (d, 1H), 7.73 (d, 1H), 7.51-7.20
(m, 8H), 7.13 (d, 1H), 7.01 (s, (1H).

Example 87

Preparation of N-r2-hvdroxv-4-cvanophenvn-N'-r2-methvlphenvn urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methylphenyl] urea was prepared from 2-
amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/

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hexane( 1/20) and filtering. (90mg, 75%). *H NMR (CD3OD): d 8.25 (d, 1H), 7.59 (d,
1H). 7.26-7.00 (m, 5H), 2.30 (s, 3H).

Example 88

Preparation of N-f2-hydroxv-4-cvanophenvll-N'-f2-trifluoromethylphenyn urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-trifluoromethylphenyl] urea was prepared
from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (1 lOmg, 76%). L H NMR (CD3OD): d 8.25 (d, 1H), 7.81
(d, 1H), 7.68 (d, 1H), 7.61 (t, 1H), 7.32 (t, 1H), 7.15 (dd, 1H), 7.09 (s, (1H).

Example 89

Preparation of N42 -hvdroxv-4-cvanophenvn-N'-r3-trifluoromethvlphenvn urea

N-[2-hydroxy-4-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared
from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane( 1/20) and filtering. ( 1 14mg, 79%). l H NMR (CD3OD): d 8.30 (d, 1H), 7.92
(s, 1H), 7.60 (d, 1H), 7.47 (t, 1H), 7.29 (d, 1H), 7.18 (dd, 1H), 7.06 (s, 1H).

Example 90

Preparation of N-r2-hvdroxv-4 -cvanophenvn-N'-r4-trifluoromethvlphenvn urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[4-trifluoromethylphenyl] urea was prepared
from 2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (108mg, 75%). ! H NMR (CD3OD): d 8.31 (d, 1H), 7.68
(d, 2H), 7.59 (d, 2H), 7.20 (dd, 1H), 7.07 (s, 1H).

Example 91

Preparation of N-r2- hvdroxv-3-n-propvlphenvn-N'-r2-bromophenvn urea
a)Preparation of 2-nitro-6-n-propylphenol

2-n-propylphenol (5.00g, 36.8mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate (3.43g, 40.5mmol). The
addition of sulfuric acid (45mL/ 3M) was then made, followed by addition of a catalytic
amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic
layer was dried over MgS04 and filtered. The solvent was evaporated and

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chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the
desired product(3.2 mg, 48 %). l ¥L NMR (CD3COCD3): d 7.99 (d,lH), 7.46 dd, 1H),
6.90 (t, 1H), 2.70 <t. 2H), 1.70 (m, 2H), 1.00 (t, 3H).

b) Preparation of 2-amino-6-n-propylphenol

5 To a solution of 2-nitro-6-n-propylphenol(2g, 1 l.Ommol) in methanol( lOOmL)

was added 10% Pd/C (200 mg). The mixture was flushed with argon, then hydrogen
was bubbled through the solution for 10 min. and a hydrogen atmosphere was
maintained at balloon pressure overnight. The mixture was filtered through celite and
the celite was washed with methanol. The solvent was evaporated and chromatography
10 of the resulting solid on silica gel (5%MeOH/ CH2CI2) gave the desired product( 1 .50 g,

80.2 %). *H NMR (CD3OD): d 6.65 (m, 2H), 6.55 (t, 1H), 2.58 (t, 2H), 1.61 (m, 2H),
0.96 (t, 3H).

c) Preparation of N-[2-hydroxy-3-n-propylphenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-3-n-propyl phenyl]-N'-[2-bromo phenyl] urea was prepared from
15 2- amino-6-n-propyl phenol (302mg, 2.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (640mg,92%). l H NMR (CD3OD): d 8.00 (d, 1H), 7.58 (d,
1H), 7.32 (t, 1H), 7.26 (t, 1H), 6.96 (dd, 1H), 6.89 (t, 1H), 6.78 (d, 1H).

20 Example 92

Preparation of N-r2-hydroxy-4-ethylphenyll-N'-r2-bromophenyll urea

a) Preparation of 2-nitro-5-ethylphenol

3-ethylphenol (5.00g, 41 mmol) was dissolved in methylene chloride(40 mL)
followed by the addition of sodium nitrate (3.83g, 45 mmol). The addition of sulfuric
25 acid (50mL/ 3M) was then made, followed by addition of a catalytic amount of sodium
nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted
with methylene chloride and extracted with water. The organic layer was dried over
MgS04 and filtered. The solvent was evaporated and chromatography of the resulting

solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(1.7 g, 25 %). l H NMR
30 (CD3COCD3): d 8.02 (d,lH), 6.99 (s,lH), 6.85 (d, 1H), 2.69 (q, 2H), 1.30 (t, 3H).

b) Preparation of 2-amino-5-ethylphenol

To a solution of 2-nitro-5-ethylphenol(lg, 6.4mmol) in methanol(250mL) was
added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen was
bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at
35 balloon pressure overnight. The mixture was filtered through celite and the celite was
washed with methanol. The solvent was evaporated and chromatography of the

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resulting solid on silica gel (5%MeOH/ CH2CI2) gave the desired product(750 mg, 91
%). l H NMR (CD3OD): d 6.41-6.17 (m, 3H).

c)Preparation of N-[2-hydroxy-4-ethylphenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-4-ethylphenyl]-N'-[2-bromo phenyl] urea was prepared from 2-
5 amino-5-ethylphenol (274mg, 2.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (520 mg, 77%). *H NMR (CD3OD): d 7.96 (d, 1H), 7.62
(s, 1H), 7.56 (d, 1H), 7.30 (t, 1H), 6.96 (t, 1H), 6.82 (d, 1H), 6.76 (d, 1H).

10 Example 93

Preparation of N-r2-hvdroxv 3-phenvla minocarbonvl phenvll-N'-r2-bromophenvn urea

a) Preparation of 2-nitro-6-phenylaminocarbonylphenol

2-Phenylaminocarbonylphenol (5.00g, 23 mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate (2.20g, 25.5 mmol). The
15 addition of sulfuric acid (30mL/ 3M) was then made, followed by addition of a catalytic
amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic
layer was dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

20 desired product(2.50 g, 42 %). *H NMR (CD3COCD3): d 8.15 (d,lH), 8.09 (d,lH),
7.51 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 7.01 (t, 1H).

b) Preparation of 2-amino-6-phenylaminocarbonylphenol

To a solution of 2-nitro-6-phenylaminocarbonylphenol ( lg, 4.0 mmol) in
methanol(250mL) was added 10% Pd/C (100 mg). The mixture was flushed with
25 argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen
atmosphere was maintained at balloon pressure overnight. The mixture was filtered
through celite and the celite was washed with methanol. The solvent was evaporated
and chromatography of the resulting solid on silica gel (5%MeOH/ CH2CI2) gave the

desired product(800 mg, 91 %). l H NMR (CD3OD): d 7.73-7.57 (m, 2H), 7.43-7.27
30 (m, 3H), 7.25-7. 10 (m, 1H), 6.94 (t, 1H), 6.74 (t, 1H).

c) Preparation of N-[2-hydroxy 3-phenylaminocarbonyl phenyl]-N'-[2-bromophenyl]
urea

N-[2-hydroxy 3-Phenylaminocarbonyl phenyl]-N'-[2-bromo phenyl] urea was
prepared from 2-amino-6-phenylaminocarbonylphenol (456mg, 2.00 mmol) according
35 to the procedure in General Method B. The product was purified by precipitation from
methylene chloride/ hexane(l/20) and filtering. (800mg,94%). l H NMR (CD3OD):

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l H NMR (CD3OD): d 25 (d, 1H), 7.94 (d, 1H), 7.75-7.57 (m, 4H), 7.48-7.30 (m, 3H),
7.21 (t, 1H), 7.02 (dd. 1H), 6.92 (t, 1H).

Example 94

5 Preparation of N-r2-hydroxy-3-cyano-4-methviphenyn-N'-r2-bromophenvll urea a)
Preparation of the 2-nitro 5-methyl 6-bromo phenol

A solution of t-butyl amine(6.88 mL, 4.79 g, 2 equiv.) in methylene chloride
was treated with bromine (1.67 mL, 5.2 g, 1 equiv.) at -20 °C. The flask was then
cooled to -78 °C and the the 2-nitro 5-methyl 6-bromo phenol (5 g, 1 equiv., in

10 methylene chloride) was added drop-wise with vigrous stirring. The reaction mixture
was slowly wanned to -30 °C for 1 h, then to -10 °C for 2 hours. The reaction mixture
was then partitioned between methylene chloride and 5% aqueous acetic acid. The
organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo.
The reaction mixture was purified by flash chromatography(Ethyl acetate/ hexanes) to

15 remove dibrominated species. The 2-nitro 4-bromo 5-methyl phenol was then

selectively crystallized out of methylene chloride. A final silica gel column(5%ethyl
acetate/ hexanes) yielded desired isomer in 90% purity.(1.05 g, 14%). *H NMR
(CDCI3): d 7.95 (d, 1H, J = 10.0 Hz), 6.91 (d, 1H, J = 10.0 Hz), 2.52 (s, 3H).

b) Preparation of 2-nitro-5-methyl-6-cyanophenol

20 2-Nitro-5-methyl-6-bromophenol (100 mg, 0.433 mmol) was dissolved in

dimethyl formamide (2mL) followed by the addition of triethylamine (0. 175g, 1.73
mmol). The addition of a catalytic amount dimethylamino pyridine was then made,
followed by addition of copper (I) cyanide (155mg, 1.73mmol). The mixture was
allowed to stir at 80_C for 4 hours. The solvent was evaporated and chromatography of

25 the resulting solid on silica gel (2%MeOH/ CH2CI2) gave the desired product (70 mg,

91 %). 'HNMR (CD3COCD3): d 8.30 (d,lH), 7.15 (d.lH), 2.61 (s, 3H).

c) Preparation of 2-amino-5-methyl 6-cyanophenol

A mixture of 5-cyano-2-nitrophenol(70 mg, 0.39mmol) and tin (II) chloride
(265 mg, l.l8mmol) in ethanol(20mL) was heated at 80_C under argon. After 2 hours,
30 the starting material has disappeared and the solution was allowed to cool down and
then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid
NaOH, before being extracted with ethyl acetate. The organic phase was washed with
brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography
of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product( 175

35 mg, 86 %). l H NMR (CD3OD): d 6.87 (d, 1H), 6.75 (d,lH), 6.32 (s, 3H).

d) Preparation of N-[2-hydroxy 3-cyano 4-methyl phenyl]-N'-[2-bromophenyl] urea

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N-[2-hydroxy 3-cyano 4-methyl phenyl]-N'-[2-bromophenyl] urea was prepared
from 2-amino-5-methyl-6-cyano phenol (50mg, 0.34 mmol) according to the procedure
in General Method B. The product was purified by precipitation from methylene
chloride/ hexane(l/20) and filtering. (70mg, 60%). [ H NMR (CD3OD): d 7.92 (d,
5 1H), 7.68 (d, 1H), 7.59 (d, 1H), 7.31 (t, 1H), 7.00 (t, 1H), 6.62 (t, 1H), 2.49 (s, (3H).

Example 95

Preparation of N-r2-hvdroxv 4 -Carboxvphenvl phenvH-N'-Q-bro mophenvn
urea a)Preparation of 4-nitro-3-hydroxybenzophenone

10 3-Hydroxybenzophenone (3.00g, 15. lmmol) was dissolved in methylene

chloride(40mL) followed by the addition of sodium nitrate ( 1.42g, 16.7mmol). The
addition of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic
amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic

15 layer was dried over MgS04 and filtered. The solvent was evaporated and

chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

desired product(l. 10 g, 30 %). l H NMR (CD3COCD3): d 8.25 (d,lH), 7.86 (d,lH),
7.71 (m, 1H), 7.59 (d, 1H), 7.48 (s, 1H), 7.39 (dd, 1H).

b) Preparation of 4-amino-3-hydroxybenzophenone

20 A mixture of 4-nitro-3-hydroxybenzophenone (900 mg, 3.7mmol) and tin (II)

chloride (2.5 g, 11.1 mmol) in ethanol(50mL) was heated at 80°C under argon. After 2
hours, the starting material has disappeared and the solution was allowed to cool down
and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid
NaOH, before being extracted with ethyl acetate. The organic phase was washed with

25 brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography
of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(685

mg, 87 %). l H NMR (CD3OD): d 7.65 (d, 2H), 7.55 (d,lH), 7.49 (t, 2H), 7.26 (s, 1H),
7.16 (dd, 1H), 6.68 (d, 1H).

c) Preparation of N-[4-Carboxyphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea
30 N-[4-Carboxyphenyl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea

was prepared from 4-amino-3-hydroxybenzophenone (330mg, 1.5 mmol) according to
the procedure in General Method B. The product was purified by precipitation from
methylene chloride/ hexane( 1/20) and filtering. (490mg, 79%). l H NMR (CD3OD): d
8.40 (d, 1H), 8.09 (d, 1H), 7.83 (d, 2H), 7.65-7.60 (m, 4H), 7.48 (s, 1H), 7.43 (d, 1H),
35 7.35 (d, (1H), 7.10 (t,lH).

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Example 96

Preparation o f N-f2-hydroxv 3-carboxvphenvl phenvl]-N'-r2-bromophenyl"|
ureaa) Preparation of 3-nitro-2-hydroxybenzophenone

2-Hydroxybenzophenone (3.00g, 15.1mmol) was dissolved in methylene
5 chloride(40mL) followed by the addition of sodium nitrate (1.42g, 16.7mmol). The
addition of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic
amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic
layer was dried over MgSCH and filtered. The solvent was evaporated and
10 chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

desired product(1.60 g, 44 %). ! H NMR (CD3COCD3): d 8.30 (d,lH), 7.86 (m,3H),
7.71 (m, 1H), 7.78 (d, 1H), 7.56 (dd 2H), 7.24 (t, 1H).

b) Preparation of 3-amino-2-hydroxybenzophenone

A mixture of 3-nitro-2-hydroxybenzophenone (600 mg, 2.5mmol) and tin (II)
15 chloride (1.7 g, 7.5mmol) in ethanol(50mL) was heated at 80°C under argon. After 2
hours, the starting material had disappeared and the solution was allowed to cool down
and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid
NaOH, before being extracted with ethyl acetate. The organic phase was washed with
brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography
20 of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(490
mg, 92 %). l H NMR (CD3OD): d 7.65-7.40 (m, 5H), 6.98 (d.lH), 6.86 (d, 1H), 6.67
(t, 1H).

c) Preparation of N-[2 -hydroxy 3-carboxyphenyl phenyl]-N'-[2-bromophenyl] urea

N-[2-hydroxy 3-carboxyphenyl phenyl]-N'-[2-bromophenyl] urea was prepared
25 from 3-amino-2-hydroxybenzophenone (250mg, 1 .20 mmol) according to the procedure
in Genera] Method B. The product was purified by precipitation from methylene
chloride/ hexane(l/20) and filtering. (200mg, 78%). *H NMR (CD3OD): d 8.35 (d,
1H), 7.96 (d, 1H), 7.72 (d, 2H), 7.65-7.50 (m, 4H), 7.35 (d, 1H), 7.30 (d, 1H), 7.01 (dd,
(lH),6.92(t. 1H).

30

Example 97

Preparation of N-r2-hvdroxv 3-benzvloxv phenvn-N'-Q- bromophenvn urea
a)Preparation of 2-nitro-6-benzyloxy phenol

2-Benzyloxyphenol (5.00g, 25.0mmol) was dissolved in methylene
35 chloride(40mL) followed by the addition of sodium nitrate (2.30g, 27.5mmol). The

addition of sulfuric acid (31mL/ 3M) was then made, followed by addition of a catalytic

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amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic
layer was dried over MgSC>4 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

5 desired product(2.6 g, 43 %). *H NMR (CD3COCD3): d 7.70 (d,lH), 7.50-7.28 (m,
5H), 7.14 (d, 1H), 6.92 (t, 1H), 5.21 (s, 2H).
b)Preparation of 2-amino-6-benzyloxy phenol

A mixture of 2-nitro-6-benzyloxy phenol ( 1 .00 g, 4. lOmmol) and tin (II)
chloride (2.75 g, 12.2 mmol) in ethanol(150mL) was heated at 80°C under argon. After

10 2 hours, the starting material had disappeared and the solution was allowed to cool

down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of
solid NaOH, before being extracted with ethyl acetate. The organic phase was washed
with brine, dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

15 desired product( 1.35 g, 88 %). *H NMR (CD3OD): d7.46 (d, 2H), 7.40-7.35 (m, 5H),
6.55 (d, 1H), 6.40 (d, 1H), 5.10 (s, 2H).

b)Preparation of N-[2-hydroxy3-benzyloxy phenyl]-N'-[2-bromophenyl] urea

N-[3-benzyloxy-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from
2-nitro-6-benzyloxy phenol (430mg, 2.00 mmol) according to the procedure in General
20 Method B. The product was purified by precipitation from methylene chloride/

hexane(l/20) and filtering. (630mg, 76%). *H NMR (CD3OD): d 7.93 (d, 1H), 7.58
(d, 1H), 7.54-7.42 (m, 3H), 7.40-7.25 (m, 4H), 7.00 (t, 1H), 6.69 (d, 2H), 5.16 (s, 2H).

Example 98

25 Preparation of N-3-r2-hvdroxv-5-indanonel-N'-r2-bromop henvll urea

a) Preparation of 2-hydroxy-3-nitro-5-indanone

2-Hydroxy-5-indanone(3.00g, 20.0mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate (1.95g, 2 LOmmol). The
addition of sulfuric acid (25mL/ 3M) was then made, followed by addition of a catalytic

30 amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic
layer was dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the
desired product(1.5 g, 39 %). l H NMR (CD3COCD3): d 7.70 (d,lH), 7.04 (d, 1H),

35 3.04 (d, 2H), 2.74 (d, 2H).

b) Preparation of 3-amino-2-hydroxy-5-indanone

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A mixture of 2-hydroxy-3-nitro-5-indanone (1.50 g, 7.80mmol) and tin (II)
chloride (5.25 g, 23.3 mmol) in ethanol(150mL) was heated at 80° C under argon.
After 2 hours, the starting material had disappeared and the solution was allowed to cool
down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of
5 solid NaOH, before being extracted with ethyl acetate. The organic phase was washed
with brine, dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the
desired product(1.00 g, 79 %). l H NMR (CD3OD): d 6.85 (d,lH), 6.45 (d, 1H), 2.95
(d, 2H), 2.60 (d, 2H).

10 c) Preparation N-3-[2-hydroxy-5-indanone]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-5-indanone]-N'-[2-bromophenyl] urea was prepared from 3-
amino-2-hydroxy-5-indanone (326mg, 2.00 mmol) according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (610mg, 85%). *H NMR (CD3OD): d 7.92 (d, 1H), 7.65

15 (m, 2H), 7.45 (t, 1H), 7.09 (t, 1H), 7.00 (d, 1H), 2.90 (d, 2H), 2.66 (d, 2H).

Example 99

Preparation of fEVN-f4-r2-rMethoxvcarbonv n ethenvll-2-hvdroxvphenvn-N'.p..
bromophenvll urea
20 a) Preparation of 4-nitro-3-hydroxycinnamic acid

3- Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate (1.70 g, 26.1 mmol). The
addition of sulfuric acid (25 mL/ 3M) was then made, followed by addition of a
catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the

25 reaction mixture was diluted with methylene chloride and extracted with water. The
organic layer was dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the
desired product(1.0 g, 26 %). *H NMR (CD3COCD3): d 8.07 (d, 1H), 7.69 (d, 1H),
7.51 (s, 1H), 7.46 (d, 2H), 6.75 (d,lH).

30 b) Preparation of 4-nitro-3-hydroxymethylcinnamate

4- Nitro-3-hydroxycinnamic acid was stirred in excess methanol with a catalytic
amount of sulfuric acid. The solvent was evaporated and chromatography of the
resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(1.0 g, 94 %).

*H NMR (CD3COCD3): d 8.17 (d, 1H), 7.69 (d, 1H), 7.52 (s, 1H), 7.45 (d, 2H), 6.75
35 (d,lH), 3.80 (s, 3H).

c)Preparation of 4-amino-3-hydroxymethylcinnamate

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A mixture of 4-nitro-3-hydroxymethylcinnamate (1.0 g, 4.50mmol) and tin (II)
chloride (3.0 g, 13.4 mmol) in ethanol(50mL) was heated at 80_C under argon. After 2
hours, the starting material had disappeared and the solution was allowed to cool down
and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid
5 NaOH, before being extracted with ethyl acetate. The organic phase was washed with
brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography
of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product (650
mg, 75 %). l H NMR (CD3OD): d7.50 (d,lH), 6.94 (s, 1H), 6.89 (d, 1H), 6.68 (d, 1H),

6.18 (d, 1H), 3.74 (s,3H).
10 d)Preparation (E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-
bromophenyl] urea

(E)-N-[4-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]
urea was prepared from 4-amino-3-hydroxymethylcinnamate (250mg, 1.3 mmol)
according to the procedure in General Method B. The product was purified by

15 precipitation from methylene chloride/ hexane( 1/20) and filtering. (300mg, 59%). *H
NMR (CD3OD): d 8.24 (d,lH), 8.05 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.42 (t, 1H),

7.21 (s, 1H), 7.19(d, lH),7.10(t, 1H)6,45 (d,lH) 3.81 (s, 3H).

Example 100

20 Preparation of (EVN-r3-r 2-^Methoxvcarbonvl) ethenvll-2-hvdroxvphenvn-N'-r2-
hromophenvn urea N'-f2-bromoohenvn urea

a) Preparation of 3-nitro-2-hydroxycinnamic acid

2- Hydroxycinnamic acid (3.00g, 18.3 mmol) was dissolved in methylene
chloride(40'mL) followed by the addition of sodium nitrate (2.21 g, 26.1 mmol). The

25 addition of sulfuric acid (30 mL/ 3M) was then made, followed by addition of a

catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the
reaction mixture was diluted with methylene chloride and extracted with water. The
organic layer was dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

30 desired product(2.0 g. 52 %). *H NMR (CD3COCD3): d 8.21 (d, 1H), 8.16 (d, 1H),
8.05 (d, 1H), 7.19 (t, 1H), 6.72 (d, 1H)

b) Preparation of 3-nitro-2-hydroxymethylcinnamate

3- nitro-2-hydroxycinnamic acid was stirred in excess methanol with a catalytic
amount of sulfuric acid. The solvent was evaporated and chromatography of the

35 resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(1.0 g, 94 %).

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L H NMR (CD3COCD3): d 8.25 (d, IH), 7.8.15 (d, 1H), 8.06 (s, 1H), 7.20 (t, 2H), 6.76
(d.lH), 3.80 (s, 3H).

c) Preparation of 3-amino-2-hydroxymethylcinnamate

A mixture of 3-nitro-2-hydroxymethylcinnamate (1.0 g, 4.5 mmol) and tin (II)
5 chloride (3.0 g, 13.4 mmol) in ethanol(50mL) was heated at 80_C under argon. After 2
hours, the starting material had disappeared and the solution was allowed to cool down
and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid
NaOH, before being extracted with ethyl acetate. The organic phase was washed with
brine, dried over MgS04 and filtered. The solvent was evaporated and chromatography
10 of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product (700
mg, 81 %). l H NMR (CD3OD): d 8.04 (d, 1H), 6.93 (d, 1H),6.79 (d, 1H), 6.71 (t, 1H),
6.43 (d, 1H), 3.72 (s, 3H).

d) Preparation(E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-
bromophenyl] urea

15 (E)-N-[3-[2-(Methoxycarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]

urea was prepared from 3-amino-2-hydroxymethylcinnamate ( 100 mg, 0.52 mmol)
according to the procedure in General Method B. The product was purified by

precipitation from methylene chloride/ hexane(l/20) and filtering. (150mg, 74%).
NMR (CD3OD): d 8. 10 (d,lH), 8.00 (d, 1H), 7.69 (d, 1H), 7.65 (d, 1H), 7.42 (t, 1H),

20 7.38 (t, 1H), 7.32 (d, 1H), 7.05 (t, 1H) 6.55 (d.lH) 3.81 (s, 3H).

Example 1Q1

Preparation of rE)-N-f3-f2-f Aminocarbonvl) ethenvn-2-h vdroxvohenvll-N'-r2-
bromophenvll urea N'-r2-bromophenvll urea

25 a)Preparation of 2-hydroxycinnamide

2-Hydroxycinnamic acid (2.00g, 12.3 mmol) was dissolved in dimethyl
formamide(lOmL) followed by the addition of benzotriazol-l-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate (5.4g, 12.3 mmol) and
triethylamine ( 1.7mL, 12.3mmol). Ammonia gas was bubbled into the reaction

30 mixture for 30 minutes. The mixture was allowed to stir for 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic
layer was dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4% MeOH/ CH2CI2) gave the
desired product(1.5 g, 75 %).

35 b)Preparation of 3-nitro-2-hydroxycinnamide

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2-Hydroxycinnamide (750 mg, 4.6 mmol) was dissolved in methylene
chloride(40mL) followed by the addition of sodium nitrate (430 mg, 5.1mmol). The
addition of sulfuric acid (7 mL/ 3M) was then made, followed by addition of a catalytic
amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
5 mixture was diluted with methylene chloride and extracted with water. The organic
layer was dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

desired product(350 mg, 36 %). ! H NMR (CD3COCD3): d 8.19 (d, 1H), 8.02 (d, 1H),
7.88 (d, 1H), 7.15 (t, 1H), 6.84 (d, 1H)

10 c)Preparation of 3-amino-2-hydroxycinnamide

A mixture of 3-nitro-2-hydroxymethylcinnamate (350 mg, 1 .7 mmol) and tin (II)
chloride (3.0 g, 13.4 mmol) in ethanol(50mL) was heated at 80° C under argon. After 2
hours, the starting material had disappeared and the solution was allowed to cool down and
then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH,

15 before being extracted with ethyl acetate. The organic phase was washed with brine, dried
over MgS04 and filtered. The solvent was evaporated and chromatography of the
resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(244 mg, 80%).
d)Preparation of (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-
bromophenyl] urea

20 (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]

urea was prepared from 3-amino-2-hydroxycinnamide (100 mg, 0.56 mmol) according
to the procedure in General Method B. The product was purified by precipitation from
methylene chloride/ hexane( 1/20) and filtering. (110 mg, 52%). *H NMR (CD3OD): d
8.00 (d,lH), 7.90 (d, 1H), 7.63 (d, 1H), 7.55 (d, 1H), 7.35 (m, 2H), 7.05 (t, 1H), 6.95

25 (t, 1H), 6.70 (d,lH) .

Example 102

Preparation of (E)-N-\4-\2-( Am inocarhonvn ethenvn-2-hvdroxvphenvll-N'-r2-
bromophenvll urea N'-r2-bro mophenvll urea

30 a)Preparation of 3-hydroxycinnamide

3-Hydroxycinnamic acid (2.00 g, 12.3 mmol) was dissolved in dimethyl
formamide(10 mL) followed by the addition of benzotriazol-l-yloxy-
tris(dimethylamino)phosphonium hexafluorophosphate (5.4g, 12.3 mmol) and
triethylamine ( 1.7 mL, 12.3mmol). Ammonia gas was bubbled into the reaction

35 mixture for 30 minutes. The mixture was allowed to stir for 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic

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layer was dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the
desired product(1.3 g, 65 %).

b) Preparation of 4-nitro-3-hydroxycinnamide

5 3-Hydroxycinnamide (750 mg, 4.6 mmol) was dissolved in methylene

chlonde(40 mL) followed by the addition of sodium nitrate (430 mg, 5. 1 mmol). The
addition of sulfuric acid (7 mL/ 3M) was then made, followed by addition of a catalytic
amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction
mixture was diluted with methylene chloride and extracted with water. The organic

10 layer was dried over MgS04 and filtered. The solvent was evaporated and

chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

desired product(240 mg, 25 %). l U NMR (CD3COCD3): d 8.09 (d, 1H), 7.49 (d, 1H),
7.26 (s, 1H), 7.16 (d, 1H), 6.71 (d, 1H)

c) Preparation of 4-amino-2-hydroxycinnamide

15 A mixture of 4-nitro-3-hydroxymethylcinnamate (300 mg, 1.40 mmol) and tin

(II) chloride (980 mg, 4.30 mmol) in ethanol(50 mL) was heated at 80_C under argon.
After 2 hours, the starting material had disappeared and the solution was allowed to cool
down and then poured into ice. The pH was made slightly basic (pH 7-8), by addition
of solid NaOH, before being extracted with ethyl acetate. The organic phase was

20 washed with brine, dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the
desired product (200 mg, 74 %).

d) Preparation(E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-
bromophehyl] urea

25 (E)-N-[3-[2-(Aminocarbonyl) ethenyl]-2-hydroxyphenyl]-N'-[2-bromophenyl]

urea was prepared from 4-amino-2-hydroxycinnamide (lOOmg, 0.56 mmol) according
to the procedure in General Method B. The product was purified by precipitation from
methylene chloride/ hexane( 1/20) and filtering. ( 125mg, 54%). *H NMR (CD3OD): d
8.05 (d.lH), 7.92 (d, 1H), 7.60 (d, 1H), 7.4 5 (d, 1H), 7.35 (t, 1H), 7.05 (m, 2H), 6.50

30 (d,lH).

Example 103

Preparation of N-f 2-hvdroxv 4-f phenyl a mino carhoxv) phenvll-N'-^-bromophenvn
urea

35 N-[2-hydroxy 4-(phenyl amino carboxy) phenyl]-N'-[2-bromophenyl] urea was

prepared from 5-(phenyl amino carboxy) 2-amino phenol (0.50 mmol) according to the

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procedure in General Method B. The product was purified by precipitation from
methylene chloride/ hexane( 1/20) and filtering. (150 mg, 70%). *H NMR (CD3OD): d
8.25 (d, 1H), 8.00 (d, 1H), 7.75 (d, 2H), 7.64 (d, 1H), 7.50 (d, 2H), 7.41 (m, 3H), 7.16
(t, 1H), 7.05 (t, 1H).

5

Example 104

Preparation of N-r4-aminocarhonvl-2-hvdroxvphenvll-N'- r2-bromophenvll urea N-[4-
Aminocarbonyl -2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from 5-
aminocarbonyl-2-amino phenol (304 mg, 0.50 mmol) according to the procedure in
10 General Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (440 mg, 62%). l H NMR (CD3OD): d 8.09 (d, 1H), 7.91
(d, 1H), 7.60 (d, 1H), 7.45 (m, 3H), 7.00 (d, 1H).

Example 105

15 Preparation of N-r2-Hvdrnxv-3.5.6-tri fluorophenvn-N'-(2-bromophenvnurea N-(2-
Hydroxy-3,5,6-trifluorophenyl)-N'-(2-bromophenyl)urea was prepared from 3,5,6-
trifluoro-2-hydroxyaniline (83 mg, 0.51 mmol) and 2-(bromophenyl)isocyanate (100
mg, 0.53 mmol) according to the procedure in General Method B. The product was
purified by preparation thin layer chromatography. EI-MS m/z 359 (M-H) .

20

Example 106

Preparation of N-f2-Hvdroxv-3 -fluoro-4-trifliioromethvlnhenvl)-N'-(2-
hromophenvDurea

N-(2-Hydroxy-3-fluoro-4-trifluoromethylphenyl)-N'-(2-bromophenyl)urea was
25 prepared from 4-trifluoromethyl-3-fluoro-2-hydroxyaniline (239 mg, 1.2 mmol) and 2-
(bromophenyl)isocyanate (243 mg, 1.2 mmol) according to the procedure in General
Method B. Removal of solvent under reduced pressure and chromatography of the
resulting solid on silica gel (hexane:ethyl acetate) gave the title compound (20 mg, 4%).
EI-MS m/z 391 (M-H)".

30

Example 107

Preparation of N-(2-Hvdroxv-3-iori ophenvlVN'-(2-bromOPhcnvl)urea

N-(2-Hydroxy-3-iodophenyl)-N'-(2-bromophenyl)urea was prepared from 3-
iodo-2-hydroxyaniline (200 mg, 0.85 mmol) and 2-(bromophenyl)isocyanate (169 mg,
35 0.85 mmol) according to the procedure in General Method B. Removal of solvent
under reduced pressure and chromatography of the resulting solid on silica gel

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(hexanexther) gave the title compound (40 mg, 1 1%). H NMR (DMSO): d 9.45 (s,
1H), 9.15 (s, 1H), 8.8 (s, 1H), 7.95 (d, 1H), 7.8 (d, 1H).7.65 (d. 1H). 7.4 (d, 1H), 7.3 (t,
lH),7.0(t, 1H), 6.65(t, 1H).

5 Example 108

Preparation of N-f2-rrr2-( , trifluoromethvnphenvnsu lfonvllaminolphenvn-N'-(2-
hromophenvDurea

a) Preparation of [2-[2-(trifluoromethyl)phenyl](sulfonamido)aniline]

The title compound was prepared according to General Method C using 2-
10 (trifluoromethyl)benzenesulfonyl chloride ( 1 equiv.). The product was purified by

chromatography on silica gel (methylene chloride:methanol) (1.04 g, 33%). EI-MS m/z

317 (M+H) +

b) Preparation of N-[2-[[[2-(trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N'-(2-
bromophenyl)urea

15 The title compound was prepared using[2-[2(trifluoromethyl)phenyl]

(sulfonamido)aniline (1.04 g, 3.2 mmol) and 2-(bromophenyl)isocyanate (652 mg, 3.2
mmol) according to General Method B. The solvent was evaporated to give the desired
urea (1.03 g, 61%). EI-MS m/z 514 (M+H) + .

20 Example 109

Preparation of N-(2-Brornophenvn-N'-r2-di methvlarninosulfonvlaminolphenvnurea

a) Preparation of [2-[l,l-(dimethylamino)]sulfonamidoaniline]

The title compound was prepared according to General Method C using
dimethylsulfamoyl chloride (1 equiv.). The product was purified by chromatography on
25 silica gel (methylene chloride: methanol). ES-MS m/z 216 (M+H) + .

b) Preparation of N-(2-Bromophenyl)-N'-[2-(dimethylaminosulfonylamino]phenyl]urea

The title compound was prepared from [2-[l,l-(dimethlyamino)sulfonamido-
aniline ( 137 mg, 0.6 mmol) and 2-(bromophenyl)isocyanate (126 mg, 0.6 mmol)
according to General Method B. The solvent was evaporated and chromatography on
30 silica gel (ethyl acetate:hexane) gave the desired urea. EI-MS m/z 413 (M+H) +

Example [ iq

Preparation of N-r2-(Phenethvls ulfonvlarnino) nhenvn-N'-(2-bromOPhenYl)urea
[2-(Phenethylsulfonamido) aniline] (example 60, 300mg, 1.09 mmol) was
35 placed in a Parr shaker bottle containing palladium ( 1 80 mg) under an argon stream.
Methanol (150 mL) was added and the container placed on a Parr shaker (55 psi) for

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several hours. The reaction mixture was filtered through Celite and the filtrate was
evaporated to give the desired aniline (269 mg, 90%). EI-MS m/z 277 (M+H) + .
b)Preparation of N-[2-(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea

The title compound was prepared from [2-(phenethylsulfonamido) aniline] (269
mg, 0.97 mmol) and 2-(bromophenyl)isocyanate (193 mg, 0.97 mmol) according to
General Method B. The desired urea was precipitated out of toluene/hexane (384 mg,
78%). EI-MS m/z 472 (M-H)".

Example 1 1 1

Preparation of N-r2-r(2-acetamido-4-methvlthi azol-5-vnsulfonvlaminnlDhenvn-N'-r?.-
bromophenynurea

a) Preparation of [2-[(2-acetamido-4-methyl-5-thiazole)sulfonarnido]aniline]

The title compound was prepared using 2-acetamido-4-methyl-5-
thiazolesulfonyl chloride (1 equiv.) according to General Method C. A solid
precipatated from the reaction mixture and was filtered to give the desired aniline (1.68
g, 52%). ES-MS m/z 327 (M+H) + .

b) Preparation of N-[2-[(2-acetamido-4-methylthiazol-5-yl)sulfonylamino]phenyl]-N'-
(2-bromophenyl)urea

The title compound was prepared from [2-[(2-acetamido-4-methyl-5-
thiazole)sulfonamido]aniline] (1.68 g,5.14 mmol) and 2-(bromophenyl)isocyanate
(1.02 g, 5. 14 mmol) according to General Method B. The product was precipitated
from ethyl acetate/hexane (220 mg, 8%). EI-MS m/z 524 (M+H) + .

Example 1 12

Preparation of N-r2-hvdroxv-4-cvanophenvn-N'-r 4-phenvlphenvn urea N-[2-
Hydroxy-4-cyanophenyl]-N'-[4-phenylphenyl] urea was prepared from 2-amino-5-
cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hexane( 1/20) and
filtering. (135 mg, 75%). l H NMR (CD3OD): d 8.33 (d, 1H), 7.71-7.29 (m, 9H), 7.25
(d, lH),7.12(s, 1H).

Example 113

Preparation of N-r2-hvdroxv-4-cvanophenvll-N'-r2.3-dichlorophenvn urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2,3 dichlorophenyl] urea was prepared from
2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/

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hexane( 1/20) and filtering. (125mg, 86%). 'H NMR (CD3OD): d 8.27 (d, 1H), 8.15
(m, 1H), 7.39-7.20 (m, 2H), 7.16 (d, 1H), 7.06 (s, 1H).

Example 1 14

5 Preparation of N-r2-hydroxy-4-cyanophenvll-N'-r2-methoxvphenvll urea

N-[2-Hydroxy-4-cyanophenyl]-N'-[2-methoxyphenyl] urea was prepared from
2-amino-5-cyanophenol (60mg, 0.45 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering (105mg, 83%). l H NMR (CD3OD): d 8.26 (d, 1H), 8.02 (d,

10 1H), 7.14 (d, 1H), 7.05 (s, 1H), 7.00-6.83 (m, 3H), 3,84 (s, 3H).

Example 1 15

Preparation of N-f2-hydroxv-4-cvanophenvl1-N'-r3-methoxvphenvl1 urea N-[2-
Hydroxy-4-cyanophenyl]-N'-[3-methoxyphenyl] urea was prepared from 2-amino-5-
15 cyanophenol (60mg, 0.45 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/ hexane( 1/20) and
filtering. (102mg, 80%). l H NMR (CD3OD): d 8.25 (d, 1H), 7.25-7.08 (m, 3H), 7.04
(s, 1H), 6.90 (t, 1H), 6.58 (d, 1H).

20 Example 1 16

Preparation of N-r2-hvdroxv-5-fluorophenvl1-N'-r2 -bromophenvn urea

a) Preparation of 2-amino-4-fluorophenol

A mixture of 4-fluoro-2-nitrophenol(lg, 4.64mmol) and tin (II) chloride (5.4 g,
24.2mmol) in ethanol(50mL) was heated at 80°C under argon. After 2 hours, the
25 starting material had disappeared and the solution was allowed to cool down and then
poured into ice. The pH is made slightly basic (pH7-8), by addition of solid NaOH,
before being extracted with ethyl acetate. The organic phase was washed with brine,
dried over MgS04 and filtered. The solvent was evaporated and chromatography of the
resulting solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(622 mg, 85

30 %). *H NMR (CD3OD): d 6.51 (dd, 1H), 6.32 (dd, 1H), 6.17 (ddd, 1H).

b) Preparation of N-[2-hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea

N-[2-Hydroxy-5-fluorophenyl]-N'-[2-bromophenyl] urea was prepared from 2-
amino-6-fluoro phenol (254mg, 2.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
35 hexane( 1/20) and filtering. (520mg,80%). l H NMR (CD3OD): d 7.88 (d, 1H), 7.79
(dd, 1H), 7.57 (d, 1H), 7.31 (t, 1H), 7.00 (t, 1H), 6.76 (dd, 1H), 6.57 (ddd,lH).

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Example 1 17

Preparation of N-r2-hvdroxy-5-trifluoromethvIphenvn-N'-r2 -bromophenvll urea

a) Preparation of 2-amino-4- trifluoromethylphenol

5 A mixture of 4-trifluoromethyl-2-nitrophenol( 1 .0 g, 4.8mmol) and tin (II)

chloride (5.4 g, 24.2 mmol) in ethanol(150mL) was heated at 80°C under argon. After
2 hours, the starting material had disappeared and the solution was allowed to cool
down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of
solid NaOH, before being extracted with ethyl acetate. The organic phase was washed

10 with brine, dried over MgS04 and filtered. The solvent was evaporated and

chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the
desired product(708 mg, 83 %). l H NMR (CD3OD): d 6.87 (s, 1H), 6.80 (d, 1H), 6.69
(d, 1H).

b) Preparation of N-[2-hydroxy-5-trifluoromethylphenyl]-N'-t2-bromophenyl] urea

15 N-[2-hydroxy-5-trifluoromethylphenyl]-N'-[2-bromophenyl] urea was prepared

from 2-amino-4-trifluoromethylphenol (354mg, 2.00 mmol) according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (490mg, 65%). l H NMR (CD3OD): d 8.40 (s,
1H), 7.94 (d, 1H), 7.60 (d, 1H), 7.35 (t, 1H), 7.18 (d, 1H), 7.03 (t, 1H), 6.95 (d, 1H).

20

Example 118

Preparation of N-r2-hvdroxvphenvn-N'- f2-bromophenvn urea

N-[2-hydroxyphenyl]-N'-[2-bromo phenyl] urea was prepared from 2- arnino-
phenol (141mg, 1.30 mmol) according to the procedure in General Method B. The
25 product was purified by precipitation from methylene chloride/ hexane(l/20) and
filtering. (300mg,75%). *H NMR (CD3OD): d 8.05 (d, 1H), 7.49 (d, 1H), 7.25 (t,
2H), 6.96 (t, 1H), 6.90 (t, 2H), 6.68 (t, 1H).

Example 1 19

30 Preparation of N-rtrans-3 -stvrl 2-hvdroxv DhenvH-N'-^-bromophenvn

urea a)Preparation of trans-6-styrl-2-nitrophenol

Trans-2-styrlphenol (500 mg, 2.55 mmol) was dissolved in methylene

chloride(40mL) followed by the addition of sodium nitrate (240 mg, 2.81mmol). The

addition of sulfuric acid (3 mL of 3M) was then made, followed by addition of a
35 catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the

reaction mixture was diluted with methylene chloride and extracted with water. The

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organic layer was dried over MgS04 and filtered. The solvent was evaporated and
chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

desired product (200 mg, 36 %). l H NMR (CD3COCD3): d 8.05 (d, 1H), 7.90 (d,

2H),7.65-7.20 (m,7H),7.00 (t,lH).
5 b)Preparation of trans-6-styrl-2-aminophenol

A mixture of trans-6-styrl-2-nitrophenol (200 mg, 0.83 mmol) and tin (II)

chloride (560 mg, 2.60 mmol) in ethanol(50mL) was heated at 80° C under argon.

After 2 hours, the starting material has disappeared and the solution was allowed to cool

down and then poured into ice. The pH is made slightly basic (pH7-8), by addition of
10 solid NaOH, before being extracted with ethyl acetate. The organic phase was washed

with brine, dried over MgS04 and filtered. The solvent was evaporated and

chromatography of the resulting solid on silica gel (4%MeOH/ CH2CI2) gave the

desired product (50 mg, 29 %). l K NMR (CD3OD): d 7.5 1 (m, 3H), 7.29 (m, 3H),7.1 1
(t, 1H), 7.00 (m, 2H), 6.69 (m, 2H).

15 c)Preparation of N-[trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea

N-[trans-3-styrl-2-hydroxyphenyl]-N'-[2-bromophenyl] urea was prepared from
trans-6-styrl-2-aminophenol (35mg, 0.17 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(l/20) and filtering. (36mg, 53%). *H NMR (CD3OD): d7.97 (d, 1H), 7.62-

20 7.48 (m, 4H), 7.45-7.26 (m, 5H), 7.25 (t, 1H), 7.15 (d, 1H), 7.01 (t, 1H), 6.88 (t 2H).

Example 120

Preparation of N-r2-hvdroxv-3.4-dichlorophenvll-N'-r2-methoxvphenvll urea

N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-methoxyphenyl] urea was prepared
25 from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the
procedure in General Method B. The product was purified by precipitation from
methylene chloride/ hexane(l/20) and filtering. (125mg,77%). *H NMR (CD3OD): d
8.02 (d, 1H), 7.79 (d, 1H), 7.05-6.86 (m, 4H), 3.92 (s, 3H).

30 Example 121

Preparation of N- r2-hvdroxv-3.4-dichlorophenvn-N'-r4-methoxvphenvn urea

N-[2-hydroxy-3,4-dichlorophenyl]-N'-[4-methoxyphenyl] urea was prepared
from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the
procedure in General Method B. The product was purified by precipitation from

35 methylene chloride/ hexane(lequiv./20equiv.) and filtering. (120mg, 74%). *HNMR
(CD3OD): d 7.89 (d, 1H), 7.35 (d, 2H), 6.99 (d, 1H), 6.90 (dd, 2H), 3.80 (s, 3H).

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Example 122

Preparation of N-r2-hydroxv-3.4-dichlorophenyll-N'-f3-trifluoromethylphenvn urea

N-[2-hydroxy-3,4-dichlorophenyl]-N'-[3-trifluoromethylphenyl] urea was
prepared from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according
to the procedure in General Method B. The product was purified by precipitation from

methylene chloride/ hexane(lequiv./20equiv.) and filtering. (130mg, 71%). ^HNMR
(CD3OD): d 7.96 (d, 2H), 7.60 (d, 1H), 7.48 (t, 1H), 7.30 (d, 1H), 7.00 (d, 1H).

Example 123

Preparation of N-r2-hv droxv-3.4-dichlorophenvn-N'-r2-phenvlphenvn urea

N-[2-hydroxy-3,4-dichlorophenyl]-N'-[2-phenylphenyl] urea was prepared from
2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the
procedure in General Method B. The product was purified by precipitation from

methylene chloride/ hexane( lequiv./20equiv.) and filtering. ( 1 lOmg, 59%). 1 H NMR
(CD3OD): d 7.77 (d, 1H), 7.73 (d, 1H), 7.53-7.14 (m, 8H), 6.95 (d, 1H).

Example 124

Preparation of N-r2-hvd roxv-3.4-dichlorophenvn-N'-r2.3-dichlorophenvn urea

N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,3-dichlorophenyl] urea was prepared
from 2-amino-5,6-dichlorophenol (80mg, 0.50 mmol, example 82b) according to the
procedure in General Method B. The product was purified by precipitation from

methylene chloride/ hexane(lequiv./20equiv.) and filtering. (130mg, 71%). H NMR
(CD3OD): d 8.06 (dd, 1H), 7.91 (d, 1H), 7.25 (m, 2H), 7.00 (d, 1H).

Example 125

Preparation of N-r2-hvdroxv-4-»sopropvlphenvll-N'-r3-trifluoromethvlphenvn urea
a)Preparation of 2-nitro-5-isopropylphenol

3-isopropylphenol (3.00g, 22 mmol) was dissolved in methylene chloride(40ml)
followed by the addition of sodium nitrate (2.06g, 24mmol). The addition of sulfuric
acid (25mL/ 3M) is then made, followed by addition of a catalytic amount of sodium
nitrite. The mixture was allowed to stir. After 24 h, the reaction mixture is diluted with
methylene chloride and extracted with water. The organic layer is dried over MgS04
and filtered. The solvent was evaporated and chromatography of the resulting solid on
silica gel (4%MeOH/ CH2CI2) gave the desired product(1.09g, 27 %). *H NMR
(CD3COCD3): d 7.95 (d,lH), 7.62 (d,lH), 7.1 1 (d, 1H), 2.95 (m, 1H), 1.24 (d, 6H).

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10

15

20

25

30

b) Preparation of 2-amino-5-isopropylphenol

To a solution of 2-nitro-5-isopropylphenol(lg, 6.4 mmol) in methanol(50 mL)
was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen
was bubbled through the solution for 10 min. and a hydrogen atmosphere was
maintained at balloon pressure overnight. The mixture was filtered through celite and
the celite was washed with methanol. The solvent was evaporated and chromatography
of the resulting solid on silica gel (5%MeOH/ CH2CI2) gave the desired product(775

mg, 93 %). l H NMR (CD3OD): d 6.71-6.44 (m, 3H), 2.73 (m, 1H), 1.20 (d, 6H).

c) Preparation of N-[2-hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea

N-[2-hydroxy-4-isopropylphenyl]-N'-[3-trifluoromethylphenyl] urea was
prepared from 2-amino-5-isopropylphenol (75mg, 0.50 mmol) according to the
procedure in General Method B. The product was purified by precipitation from
methylene chloride/ hexane(lequiv./20equiv.) and filtering. (140mg, 83%). NMR
(CD3OD): d 7.91 (d, 2H). 7.62 (d, 1H), 7.47 (t, 1H), 7.39 (d, 1H), 6.75 (s, 1H), 6.72 (d,

1H), 2.80 (m, 1H), 1.21 (d, 6H).

Preparation of N-r2-hvdroxv-3-naphthvn-N'-r2.3-dichl nrophenvl1 urea

N-[2-hydroxy-3-naphthyl]-N'-[2,3-dichlorophenyl] urea was prepared from 3-
amino 2-naphthol (160mg, 1.00 mmol) according to the procedure in General Method
B. The product was purified by precipitation from methylene chloride/
hexane( lequiv./20equiv.) and filtering. (285mg, 82%). l H NMR (CD3OD): d 8.48 (s,
1H), 8.10(d, 1H), 7.68 (d, 1H), 7.57 (d, 1H), 7.40-7.23 (m, 4H), 7.18 (d, 1H).

Preparation of N-r2-fr2.3-Dichlorot hien-5-vmsulfonvlaminolphenvn-N'-f2-
bromophenvhurea

a) Preparation of [2-[(2,3-Dichlorothien-5-yl)]sulfonylaminoaniline]

The title compound was prepared according to General Method C using 2,3-
dichlorothiophene-5-sulfonyl chloride ((1 eq). The product was purified by flash
chromatography on silica gel (ethyl acetate/hexane 20/80-methylene chloride:methanol
90/10) (1.25 g, 39 %). EI-MS m/z 321 (M-H)~

b) Preparation of N-[2-[(2,3-DichJorothien-5-yl)]suIfonylamino]phenyl]-N'-(2-
bromophenyl)urea

The title compound was prepared from [2-[(2,3-dichlorothien-5-
yl)]sulfonylaminoaniline (1.25 g,3.9 mmol) and 2-(bromophenyl)isocyanate (768 mg.

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3.9 mmol) according to General Method B. The product was purified by flash
chromatography on silica gel (ethyl acetate :hexane 30/70) (272 mg, 13 %) EI-MS m/z
520 (M-H)~

Preparation of N-r2-f(3.5-Bistrifluoromethylphenynsulfonvlaminolphenyl1-N'-(2-
bromophenvDurea

a) Preparation of [2-(3,5-Bistrifluoromethylphenyl)sulfonylaminoaniline]

The title compound was prepared according to General Method C using 3,5-
10 (bistrifluoromethyl)phenylsulfonyl chloride (1.28 g, 4.1 mmol) and o-phenylenediamine
(441 mg, 4.1 mmol). The product was purified by flash chromatography on silica gel
(methylene chloride: methanol 95/5) (61 1 mg. 39 %). EI-MS m/z 383 (M-H)"

b) Preparation of N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyi]-N'-(2-
bromophenyl)urea

15 The title compound was prepared from [2-(3,5-bistrifluoromethylphenyl)

sulfonylaminoaniline (591 mg, 1.5 mmol) and 2-bromophenylisocyanate (305 mg, 1.5
mmol) according to General Method B. The product was purified by flash chroma-
tography on silica gel (ethyl acetate :hexane 30/70) (10 mg, 1 %).EI-MS m/z 580 (M-H)"

20 Example 129

Preparation of N-r2-ff2-Benzvnsulfonvlamino1-(5-trifluorom ethvnphenvn-N'-(2-
brpmophenyDurea

a) Preparation of [(4-Benzylsulfonylamino)-(3 -nitro)-benzotrifluoride]

4-Amino-3-nitro-benzotrifluoride (1.0 g, 4.85 mmol) was mixed in DMF and
25 the reaction mixture was cooled to 0°C. Sodium hydride (175 mg, 7.28 mmol) was
added to the cold mixture and allowed to mix for ten minutes ( a deep red color was
noted). Toluenesulfonyl chloride (925 mg, 4.85 mmol) was added ( reaction color
changed to yellow) and the reaction was mixed for sixteen hours at room temperature.
The reaction was quenched in NH4CI and extracted with ethyl acetate :hexane ( 1:1).

30 The product was purified by flash chromatography on silica gel ( ethyl acetate: he xane
30/70) (878 mg, 52 %) EI-MS m/z 359 (M-H)".

b) Preparation of [(4-Benzylsulfonylamino)-(3-amino)-benzotrifluoride]

. [(4-Benzylsulfonylamino)-(3-nitro)-benzotrifluoride (230 mg, 0.64 mmol) was
mixed in methanol and poured into a Parr bottle. Palladium on carbon (15 mg) was
35 added under an argon stream. The reaction mixture was placed on a Parr shaker ( 55

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psi, H2) for several hours. The reaction mixture was filtered through Celite to give the
title compound. (210 mg, 99%) EI-MS m/z 329 (M-H)~.

^Preparation of N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-
bromophenyl)urea

5 The title compound was prepared from [(4-benzylsulfonylamino)-(3-amino)-

benzotrifluoride (210 mg, 0.64 mmol) and 2-bromophenylisocyanate (126 mg, 0.64
mmol) according to the procedure in General Method B. The product was purified by
flash chromatography on silica gel (ethyl acetate :hexane 30/70) (70 mg, 21%) EI-MS
m/z 526 (M-H)*

10

Example 13Q

Pre paration of N-ri-f2-f 3-Nitmphenvnsu 1fonvlaminn1phenvl1-N'-(2-bromODhenvl)urca _

a) Preparation of [2-((3-Nitrophenyl)sulfonylamino)aniline]

The title compound was prepared according to General Method C using 3-
15 nitrobenzenesulfonyl chloride (1 eq). The product was purified by flash chromatogrphy
on silica gel (methylene chloride.methanol 96/4).(1.07 g, 37 %) EI-MS m/z 294 (M+H) +

b) Preparation of N-[2-[(3-Nitrophenyl)sulfonylamino]phenyl]-N , -(2-bromophenyl)urea

The title compound was prepared from [2-(3-nitrophenyl)sulfonylaminoaniline]
(590 mg, 2.0 mmol) and 2-(bromophenyl)isocyanate(398 mg, 2.0 mmol) according to
20 the procedure in General Method B. The product was purified by flash chromatography
on silica gel (ethyl acetate :hexane 30/70) (400 mg, 40%). EI-MS m/z 489 (M-H)"

Fxamnte 131

preparation of N-r2-r2-(4-Phenftvvphenvns nlfnnvlamino1nhenvn-N'-(2-bromQPhenvl)
25 urea

a) Preparation of [2-((4-Phenoxyphenyl)sulfonylamino)aniline]

The title compound was prepared according to General Method C using 4-
phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenylenediamine (300 mg,
2.77 mmol). The reaction mixture was partitioned between water (200 ml) and
30 toluene:methylene chloride ( 1 :3). The organic phase collected and the methylene
chloride evaporated leaving the toluene. Hexane added and the product precipatated
from solution. (3 17 mg, 34 %) EI-MS m/z 341 (M+H) +

b) Preparation of N-[2-[(4-Phenoxyphenyl)sulfonylamino]phenyl]-N'-(2-

bromophenyl)urea

35 The title compound was prepared from [2-(4-phenoxyphenyl)sulfonyl

aminoaniline (276 mg, 0.8 mmol) and 2-(bromophenyl)isocyanate (161 mg, 0.8 mmol)

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according to the procedured in General Method B. The product was purified by flash
chromatography on silica gel (ethyl acetate :hexane 30/70) (240 mg, 55 %) EI-MS m/z
536 (M-H)"

5 Example 13?

Preparation of N-rr2-(lS)-10-Camphorsulfonvlaminolp henvn-N'-<-2-bromophenvl^irea

a)Preparation of 2-((lS)-10-Camphorsulfonylamino)aniline

The title compound was prepared according to General Method C using (1S)(+)-

10 10-Camphorsulfonyl chloride ( 1. 16 g, 4.6 mmol) and o-phenylenediamine (500 mg, 4.6
mmol). The reaction mixture was partitioned between water (200 ml) and
toluene:methylene chloride (1:3). The organic phase was separated and the methylene
chloride evaporated leaving the toluene. Hexane was added and solid precipitated from
solution. (130 mg, 9%) EI-MS m/z 323 (M+H) +

1 5 b)Preparation of N-[[2-( IS)- 10-Camphorsulfonylamino]phenyl]-N'-(2-
bromophenyl)urea

The title compound was prepared from [2-(lS)-10-
camphorsulfonylamino]aniline (130 mg, 0.4 mmol) and 2-(bromophenyl)isocyanate (80
mg, 0.4 mmol) according to the procedure in General Method B. The solvent was

20 evaporated and product was precipitated from methylene chloride:hexane. (200 mg, 95
%). EI-MS m/z 518 (M-H)"

Example 133

Preparation of N-ff2-('lR)-10-Camphor S ulfonvlaminolph envn-N , -r2-hromophenvnurea

25

a) Preparation of 2-((lR)-10-Camphorsulfonylamino)aniline

The title compound was prepared according to General Method C using ( 1 R)(-)-
10-camphorsulfonyl chloride (1.16 g, 4.6 mmol) and o-phenylenediamine (500 mg, 4.6
mmol). The reaction mixture was partitioned between water (200 mL) and
30 toluene:methylene chloride(l :3). The organic phase was separated and the methylene
chloride evaporated leaving the toluene. Hexane was added and the product
precipitated from solution. (563 mg, 38%). EI-MS m/z 323 (M+H) +

b) Preparation of N-[[2-(lR)-10-Camphorsulfonylamino]phenyl]-N'-(2-
bromopheny 1 )urea

35 The title compound was prepared from [l-( 1R)-10-

camphorsulfonylaminoaniline] (563 mg, 1.75 mmol) and 2-(bromophenyl)isocyanate

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(346 mg, 1.75 mmol) according to the procedure in General Method B. The product
was purified by flash chromatography on silica gel (ethyl acetate :hexane 30/70) (263
mg, 29 %) EI-MS m/z 518 (M-H)"

5 Example 134

Preparation of N-f2-f2-f2-Nitro-(4-trifluoromethv nphenvl'lsi]lfonvlaminolphenvl-N'-r2-
bromophenvPurea

a) Preparation of [2-[(2-Nitro)-(4-trifluoromethyl)phenyl]sulfonylamino]aniline

The title compound was prepared according to General Method C using 2-nitro-
10 4-(trifluoromethyl)benzenesulfonyl chloride (1 eq). The product was purified by flash
chromatography on silica gel ( methylene chloride: methanol 96/4) (875 mg, 25 %) EI-
MS m/z 362 (M+H) +

b) .Preparation of N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-
(2-bromophenyl)urea

15 The title compound was prepared from [2-[(2-nitro)-(4-trifluoromethyl)

phenyl]sulfonylamino]aniline (740 mg, 2.1 mmol) and 2-(bromophenyl)isocyanate
(406 mg, 2.1 mmol) according to General Method B. The product was purified by flash
chromatography on silica gel (ethyl acetate:hexane 30/70). The product was further
purified by recrystallization in ethyl acetate :hexane. (320 mg, 28 %) EI-MS m/z 557

20 (M-H)"

Example 135

Preparation of N-(2-hvdroxv-4-azidophenvlVN'-(2-io doDhenvnurea

a) Preparation of N-(2-hydroxy-4-aminophenyl)-N'-(2-iodophenyl)urea

To a solution of N-(2-hydroxy-4-nitrophenyl)-N'-(2-iodophenyl)urea (220 mg,
25 0.55 mmol) in ethanol (15 mL), Tin chloride (522 mg, 2.75 mmol) was added. The

reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The
reaction mixture was basified to pH 8 with aq. NaHC03 then extracted with ethyl
acetate (3x). The organic extracts were combined, dried over MgS04, filtered and
concentrated under reduced pressure to give product (180 mg, 89%). EI-MS m/z 370
30 (M+H) +

b) Preparation of N-(2-hydroxy-4-azidophenyl)-N'-(2-iodophenyl)urea

The N-(2-hydroxy-4-aminophenyl)-N'-(2-iodophenyl)urea(77 mg, 0.21 mmol)
was added to HCI/H2O (0.21 mL/0.42 mL), and cooled to 0°C. Sodium nitrate (14.5
mg, 0.21 mmol) was added to the reaction mixture. The reaction mixture was stirred at
35 0°C for 30 minutes. Sodium azide ( 14 mg, 0.21 mmol) was added to reaction mixture
and it was warmed to room temperature. The reaction mixture was stirred at room

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temperature for 18 hours. Then it was extracted with three times by ethyl acetate. The
organic extracts were combined, dried over MgS04, filtered and concentrated under

reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl

acetate; 5:1) gave product (20 mg, 24%). EI-MS m/z 396 (M+H) +

5

Example 136

Preparation of N-r2-hvdroxy-3-azidophenvl)-N'-(2-bromophenynurea

a) Preparation of N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea

To a solution of N-(2-hydroxy-3-nitrophenyl)-N'-(2-bromophenyl)urea (300 mg,
10 0.85 mmol) in ethanol (20 mL), Tin chloride (958 mg, 4.25 mmol) was added. The

reaction mixture was stirred at reflux for 16 hours then cooled to room temperature. The
reaction mixture was basified to pH 8 with aq. NaHC03 then extracted with ethyl
acetate (3x). The organic extracts were combined, dried over MgS04, filtered and
concentrated under reduced pressure to give product (274 mg, 99%). EI-MS m/z 323
15 (M+H) +

b) Preparation of N(2-hydroxy-3-azidophenyl)-N'-(2-bromophenyl)urea

The N-(2-hydroxy-3-aminophenyl)-N'-(2-bromophenyl)urea(274 mg, 0.85
mmol) was added to HCI/H2O (0.85 mL/1.7 mL), cooled to 0°C. Sodium nitrate (58.6
mg, 0.85 mmol) was added to the reaction mixture. The reaction mixture was stirred at
20 0°C for 30 minutes. Sodium azide (55 mg, 0.85 mmol) was added to reaction mixture
and it was warmed to room temperature. The reaction mixture was stirred at room
temperature for 18 hours then it was extracted with three times with ethyl acetate. The
organic extracts were combined, dried over MgS04, filtered and concentrated under

reduced pressure and chromatography of the resulting solid on silica gel (hexane : ethyl
25 acetate; 5: 1) gave product (210 mg, 71%). EI-MS m/z 349 (M+H) + .

Example 137

Preparation of N-f2-hvdroxv-3-cvanophenvll-N'-r2-methoxvphenvn urea

N-[2-hydroxy-3-cyanophenyl]-N'-[2-methoxyphenyl] urea was prepared from 2-
30 amino-6-cyanophenol ( 1 34mg, 1 .00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (230 mg, 8 1%). *H NMR (CD3OD): d 8.06 (d,
1H), 7.79 (d, 1H), 7.49-7.35 (m, 2H), 7.05-6,87 (m, 3H), 3.95 (s, 3H).

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Example 1 38

Preparation of N-r2-hvdroxv-3-cvanophenvn-N^n-tri fluoromethvlphenvn urea

N-[2-hydroxy-3-cyanophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared
from 2-amino-6-cyanophenol (134mg, 1.00 mmol, example 83a) according to the
5 procedure in General Method B. The product was purified by precipitation from

methylene chloride/ hexane(lequiv./20equiv.) and filtering. (280mg, 87%). NMR
(CD3OD): d 8.10 (d, 1H), 7.96 (s, 1H), 7.54 (d, 1H), 7.55-7.25 (m, 3H), 7.01 (t, 1H).

Example 1 39

10 Preparation of N-r2-hydroxy-3-cyanophenyl1-N'-r2-phenvlDhenvn urea

N-[2-hydroxy-3-cyanophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-
amino-6-cyanophenol (134mg, 1.00 mmol, example 83a) according to the procedure in
General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (270mg, 82%). l H NMR (CD3OD): d 7.81 (d,

15 1H), 7.75 (d, 1H), 7.56-7.15 (m, 9H), 6.91 (t, 1H).

Example 140

Preparation of N-r2-hydroxy-3-cyanophenyl1-N'-r2.3-dichlorophenyll urea N-[2-
hydroxy-3-cyanophenyl]-N'-[2,3 dichlorophenyl] urea was prepared from 2-amino-6-
20 cyanophenol (134mg, 1.00 mmol, example 83a) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
hexane( lequiv./20equiv.) and filtering. (300mg, 93%). *H NMR (CD3OD): d 8. 1 1 (d,
1H), 8.01 (d, 1H), 7.33-7.25 (m, 3H), 7.00 (t, 1H).

25 Example 141

Preparation of N-f2-hvdroxv-4-isopropvlphenvl1-N'-r 2.3-dichlorophenvn urea
N-[2-hydroxy-4-isopropylphenyl]-N'-[2,3-dichlorophenyl] urea was prepared from 2-
amino-5-isopropylphenol (150 mg, 1.00 mmol, example 128a) according to the
procedure in General Method B. The product was purified by precipitation from

30 methylene chloride/ hexane(lequiv./20equiv.) and filtering (285mg, 84%). l H NMR
(CD3OD): d 8.05 (d, 2H), 7.77 (s, 1H), 7.26 (m, 2H), 6.88 (m, 2H), 2.82 (m. 1H), 1.25

(d, 6H).

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Example 142

Preparation of N-r2-hvdroxv-4-isnpropvlphenvn-N'- r2-chloro-5-trifluoromethviphenvn
urea

N-[2-hydroxy-4-isopropylphenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea
5 was prepared from 2-amino-5-isopropylphenol (150mg, 1.00 mmol, example 128a)
according to the procedure in General Method B. The product was purified by
precipitation from methylene chloride/ hexane(lequiv./20equiv.) and filtering. (275mg,
82%). ! H NMR (CD3OD): d 8.50 (s, 1H), 7.70 (s, 1H), 7.51 (d, 1H), 7.22 (d, 1H),
6.70 (m, 2H), 6.62 (dd, 1H), 2.76 (m, (1H), 1.16 (d, 6H).

10

Example 143

Preparation of N-f2-hvdroxv -3-phenvlphenvn-N'-r2.3-dichlorophenvn urea

a) Preparation of 2-nitro-6-phenylphenol

2-phenylphenol (3.00g, 17.6mmol) was dissolved in methylene chloride(40ml)
15 followed by the addition of sodium nitrate ( 1.65g, 19.4mmol). The addition of sulfuric
acid (25ml/ 3M) was then made, followed by addition of a catalytic amount of sodium
nitrite. The mixture was allowed to stir. After 24 hrs, the reaction mixture was diluted
with methylene chloride and extracted with water. The organic layer was dried over
MgS04 and filtered. The solvent was evaporated and chromatography of the resulting

20 solid on silica gel (4%MeOH/ CH2CI2) gave the desired product(900 mg, 24 %). *H
NMR (CD3COCD3): d 8.19 (d,lH), 7.79 (d,lH), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t,
1H), 7.22 (t, 1H).

b) Preparation of 2-amino-6-phenylphenol

To a solution of 2-nitro-6-phenylphenol(900 mg, 4.2mmol) in methanol(50ml)
25 was added 10% Pd/C (100 mg). The mixture was flushed with argon, then hydrogen
was bubbled through the solution for 10 min. and a hydrogen atmosphere was
maintained at balloon pressure overnight. The mixture was filtered through celite and
the celite was washed with methanol. The solvent was evaporated and chromatography
of the resulting solid on silica gel (5%MeOH/ CH2CI2) gave the desired product(700

30 mg, 90 %). l H NMR (CD3OD): d 7.55-7.27 (m, 5H), 6.77-6.61 (m, 3H)

c) Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea

N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea was prepared from
2- amino-6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
35 hexane(lequiv./20equiv.) and filtering. (150mg,81%). *H NMR (CD3OD): d 8.06 (d,
1H).7.65 (d, 1H), 7.54 (d, 2H),7.40 (t, 2H), 7.32 (d, 1H) 7.22 (m, 2H), 7.04-6.88

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Preparation of N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea
b)N-[2-hydroxy-3-phenylphenyl]-N'-[2,3-dichlorophenyl] urea was prepared from 2-
amino-6-phenylphenol (92.5mg, 0.50 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/
5 hexane(lequiv./20equiv.) and filtering. (150 mg. 81%). l H NMR (CD3OD): d 8.06 (d,
1H),7.65 (d, 1H), 7.54 (d. 2H),7.40 (t, 2H), 7.32 (d, 1H) 7.22 (m, 2H), 7.04-6.88 (m, 2H).

Example 144

Preparation of N-r2-hvdroxv-5- nitrophenvl1-N'-f2-methoxvDhenvn urea
10 N-[2-hydroxy-5-nitrophenyl]-N'-[2-methoxyphenyl] urea was prepared from 2-

amino-4-nitrophenol (154 mg, 1.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/ hexane(
lequiv./20equiv.) and filtering. (270 mg, 89%). l H NMR (CD3OD): d 9. 10 (s, 1H),
8. 10 (d, 1H), 7.85 (d, 1H), 7.08-6.88 (m, 4H), 3.96 (s, 3H).

15

Example 145

Preparation of N-r2-hvdroxv-5-nitrophenvn-NW3-tri fluoromethvrDhenvl1 urea

N-[2-hydroxy-5-nitrophenyl]-N'-[3-trifluoromethylphenyl] urea was prepared
from 2-amino-4-nitrophenol (154 mg, 1.00 mmol) according to the procedure in
20 General Method B. The product was purified by precipitation from methylene chloride/
hexane(lequiv./20equiv.) and filtering. (290 mg, 85%). l H NMR (CD3OD): d 9.12 (s,
1H), 7.89 (d, IH), 7.68 (d, 1H), 7.55 (m, 2H), 7.45 (d, 1H), 7.00 (d, 1H).

Example 146

25 Preparation of N-r2-hvdroxv-5-nitroo henvll-N'-r2-phenvlphenvn urea N-[2-
hydroxy-5-nitrophenyl]-N'-[2-phenylphenyl] urea was prepared from 2-amino-4-
nitrophenol (154 mg, 1.00 mmol) according to the procedure in General Method B. The
product was purified by precipitation from methylene chloride/

hexane(lequiv./20equiv.) and filtering. (285 mg, 81%). *H NMR (CD3OD): d 8.09 (s,
30 1H), 7.86 (d, 1H), 7.58-7.20 (m, 9H), 6.95 (d, 1H).

Example 147

Preparation of N-r2-hvriroxv-5-n itrophenvn-N'-r2.3-dichlorophenvn urea

N-t2-hydroxy-5-nitrophenyl]-N'-[2,3-dichlorophenyl] urea was prepared from 2-
35 amino-4-nitrophenol (154 mg, 1.00 mmol) according to the procedure in General
Method B. The product was purified by precipitation from methylene chloride/

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hexane( lequiv./20equiv.) and filtering. (290 mg, 85%). H NMR (CD3OD): d 9. 1 1 (s,
1H), 8. 17 (d, 1H), 7.89 (d, 1H), 7.34 (m, 2H), 6.95 (d, 1H).

Example 148

5 Preparation of N-r2-hvdroxv-5-ethvlsulfonvlphenyn-N'-f2.3-dichlorophenvll urea
N-[2-hydroxy-5-ethylsulfonylphenyl]-N'-[2,3-dichlorophcnyl] urea was
prepared from 2-amino-4-(ethylsulfonyl)phenol (185 mg, 1.00 mmol) according to the
procedure in General Method B. The product was purified by precipitation from
methylene chloride/ hexane(lequiv./20equiv.) and filtering. (3 10 mg, 84%). NMR
10 (CD3OD): 5 8.65 (s, 1H), 8.18 (d, 1H), 7.45 (d, 1H), 7.26 (m, 2H), 7.00 (d, 1H), 3.33

(q,2H), 1.24 (t, 3H).

The following compounds of Formula (I) have been prepared in accordance with
the examples and schemes as described above:
15 Example 149 : N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-
(2-bromophenyl)ureaEI-MS m/z 527 (M-H)\

Example 150 : N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N'-(2-bromo phenyl)
ureaEI-MS m/z 426 (M+H) + ;

Example 151 : N-[2-[2-(4-Chloro-3-aminophenyl)sulfonylamino]phenyl]-N'-(2-
20 bromophenyl)urea

Example 152 : N-[2-(3-Aminophenyl)sulfonylaminophenyl]-N'-(2-bromophenyl)urea
Example 153 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2-methoxyphenyl)urea EI-MS m/z 302.3
(M-H)~.

Example 154 : N-(2-Hydroxy-3-nitrophenyl)-N'-(4-methoxyphenyl)urea urea EI-MS m/z

25 302.3 (M-H)".

Example 155 : N-(2-Hydroxy-3-nitrophenyl)-N'-(3-trifluoromethyphenyl)urea urea EI-MS
m/z 340.3 (M-H)"

Example 156 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2-phenylphenyl)urea *H NMR (DMSO),
8.83(lH,s) 8.63(lH,s), 8.41 (lH,d) 7.79 (lH,d), 7.56 (lH,d) 7.51-7.32 (6H,m) 7.23 (lH,ds)
30 7.18 (lH,d) 6.97 (lH,t)

Example 157 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2,3dichlorophenyl) EI-MS m/z 340.3 (M-
H)"

Example 158 : N-(2-Hydroxy-3-nitrophenyl)-N'-(4-phenylphenyl) EI-MS m/z 348.3 (M-
H)-

35 Example 159 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2,4-dimethoxyphenyl)urea EI-MS m/z
333.4 (M+H) + ;

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Example 160 : N-(2-Hydroxy-3-nitrophenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
EI-MS m/z 374.2 (M-H)"

Example 161 : N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-methoxyphenyl)urea EI-
MS m/z 421.3 (M-H)"

5 Example 162 : N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2-phenylphenyl)urea EI-
MS m/z 467.3 (M-H)"

Example 163 : N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(3-
trifluoromethylphenyl)urea EI-MS m/z 459.3 (M-H)"

Example 164 : N-(2-Benzenesulfonylamino-4-cyanophenyl)-N'-(2,3dichlorophenyl)urea
1 o EI-MS m/z 46 1 . 1 (M+H) + ;

Example 165 : N-(2-Hydroxy-4-amidinophenyl)-N'-(2-bromophenyl)urea *H NMR
{CD3OD): 8 8.10(1H,8) 7.92(1H,8) 7.58 (1H,5) 7.40-7.25 (3H,m) 7.02 (1H, t); EI-MS m/z

348.0 (M-H)"

Example 166 : N-(2-Hydroxy-3,4-dichloro phenyl) N'( phenyl) urea EI-MS m/z 297.0
15 (M+H)+

Example 167 : N-(2-Hydroxy 4-cyano phenyl) N'( phenyl) urea EI-MS m/z 284.0 (M+H) +
Example 168 : N-(2-Hydroxyphenyl 3-carboxylic acid)N'( phenyl) urea EI-MS m/z 273.0
(M+H)+

Example 169 : N-(2-Hydroxy-3-nitrophenyl)-N'-phenylurea EI-MS m/z 274.0 (M+H) +
20 Example 170 : N-(2-hydroxy-3-cyano phenyl ) N'(phenyl) urea EI-MS m/z 254.0 (M+H) +
Example 171 : N-(2-Hydroxy-3-cyano-4-chlorophenyl)-N'-(2-bromophenyl)urea EI-MS
m/z 264.2 (M-H)'

Example 172 : N-(2-Hydroxy-3-fluorophenyl)-N'-(phenyl)urea EI-MS m/z 247.0 (M+H) +
Example 173 : N-(2-Hydroxy-3,4-difluorophenyl)-N'-(phenyl)urea EI-MS m/z 265.0
25 (M+H)+

Example 174 : N-[2-(Benzylsulfonylamino)-4-cyanophenyl]-N'-(2,3-dichlorophenyl)urea
EI-MS m/z 473.0 (M-H)"

Example 175 : N-[2-(Phenylsulfonylamino)-4-trifluoromethylphenyl]-N'-(2,3-
dichlorophenyDurea EI-MS m/z 502.0 (M-H)"
30 Example 176 : N-[2-(3-Pyridinesulfonylamino)-4-cyanophenyl]-N'-(2,3-

dichlorophenyl)urea l H NMR (CD3OD): 8 8.76(lH,s) 8.70(iH,d), 8.19 (lH,d) 8.00
(lH,dd) 7.92 (lH.dd) 7.54 (lH.dd) 7.54 (1H, dd) 7.45 (lH.dd) 7.19 (lH,d) 7.17 (1H, s)
6.86 (lH,d)

Example 178 : N-[2-(5-Isoquinolinesulfonylamino)-4-cyanophenyl]-N'-(2,3-
35 dichlorophenyl)urea l H NMR (CD3OD): 89.37 (lH,s) 8.51-8.39 (3H,m) 8.29 (lH,d) 8.00
(lH.dd) 7.93 (lH,d) 7.67 (1H, t) 7.50 (lH,dd) 7.25 (lH.d) 7.24 (lH,s) 6.9i (lH.d)

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Example 179 : N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-chlorophenyl)urea EI-
MS m/z 427.0 (M+H)+

Example 180 : N-[(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-fluoro phenyl) urea EI-MS
m/z 41 1.0 (M+H)+

Example 181 : N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-thiomethylphenyl)urea
EI-MS m/z 439.0 (M+H)+

Example 182 : N-[2-(Phenylsulfonylamino)-4-cyano phenyI]-N'-(2-
trifluoromethoxyphenyl)urea EI-MS m/z 477.0 (M+H) +
Example 183 : N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-
trifluoromethylphenyl)urea EI-MS m/z 461.0 (M+H) +

Example 184 : N-[2-(Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methylphenyl) urea EI-
MS m/z 407.0 (M+H)+

Example 185 : N-[2-(Phenylsulfonylamino)-4-cyano phenyl]-N'-(2-methoxy 3-chloro
phenyl) urea EI-MS m/z 457.0 (M+H) +

Example 186 : N-[2-(4-cyanophenyl)-N'-(3-fluoro phenyl) urea EI-MS m/z 409.0 (M-H)"
Example 187 : N-(2-Thiophenesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
; m.p. : 138.5 - 139.2

Example 1 88 : N-[(2-Pyrid-2-yl)thiophene-5-sulfonylamino-4-cyanophenyl]-N'-(2,3-
dichlorophenyl)urea ; m.p. : 147.5 - 148.3

Example 189 : N-[(2-Acetarnino-4-methyl-5-thiazolesulfonylamino-4-cyanophenyl]-N'-
(2,3-dichlorophenyl)urea EI-MS m/z 540.4 (M+H) +

Example 190 : N-((2-aminosulfonylphenyl) 4-cyano phenyl) N'-(2-methyl-3-chloro phenyl)
urea EI-MS m/z 439.0 (M-H)-

Example 191 : N-(2-benzenesulfonylamino-3-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
l H NMR (DMSO): 5 10.00 (lH,s) 9.05 (lH.s) 8.93 (lH.s) 8.19 (lH.dd) 8.00 (lH,dd) 7.72-
7.42 (7H,m) 7.35 (lH,d) 7.32 (lH.s)

Example 192 : N-[(Benzylsulfonylamino)-5-cyanophenyl]-N'-(2,3-dichlorophenyl)urea EI-
MS m/z 474.0 (M-H)-

Example 193 : N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-nitrophenyl)urea EI-MS
m/z 438.0 (M-H)-

Example 194 : N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-
nitrophenyl)urea EI-MS m/z 450.0 (M-H)"

Example 195 : N-[(2-Phenylsulfonylamino)-4-cyanophenyl]-N'-(2-methyl-3-
aminophenyl)urea EI-MS m/z 422.0 (M+H)+

Example 196 : N-[(2-Phenylsulfonylamino)-4-cyanophenyl)-N'-(2-arninophenyl)urea EI-
MS m/z 408.0 (M+H)+

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Example 197 : N-(2-(2-pyridinesulfonylamino-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
l H NMR (CD3OD): 5 8.90 (lH,d) 8.33 (lH.d) 8.14(2H,m) 7.99 (lH,d) 7.78 (lH,dd) 7.67
(lH.dd) 7.40 (lH.d) 7.39 (lH,s) 7.18 (lH,s)

Example 198 : N-(2-Benzenesulfonylamino-3-trifluoromethylphenyl-N'-(2,3-
5 dichlorophenyl)urea *H NMR (CD3OD): 5 8.08 (lH,.dd) 7.90 (lH,dd) 7.78 (2H,m) 7.50
(2H,d) 7.41 (3H,m) 7.27 (2H,d)

Example 199 : N-(4-benzenesulphonylthiophene-2-sulphonylamino-4-cyanophenyl)-N'-
(2,3-dichlorophenyl)urea EI-MS m/z 609.0 (M+H) +

Example 200 : N-(2-trifluoromethylbezenesulfonylamino-4-cyanophenyl)-N'-(2,3-
10 dichlorophenyDurea EI-MS m/z 527.1 (M+H)+

Example 201 : N-(2-Hydroxy-4-cyanophenyl)-N'-(2,3-methylenedioxyphenyl)urea *H
NMR (CD3OD): 5 8.22 (lH.d) 7.49 (lH,d) 7.18 (lH.d) 7.08 (lH,s) 6.82 (lH.t) 6.61(lH,d)

6.00 (2H,s)

Example 202 : N-[2-(2-nitrophenylthio)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea; m.p. :
15 204.1 - 205.3

Example 203 : N-(2-hydroxy-3-trifluoromethylphenyl)-N'-(2,3-dichlorophenyl)urea; m.p. :
204.3 - 205.2

Example 204 : N-(2-hydroxy-3-trifluoromethylphenyl)-N'-(2-phenylphenyl)urea m.p. 136.7
- 137.3

20 Example 205 : N-(2-Hydroxy-4-nitrophenyl)-N'-(2-benzylphenyl)urea EI-MS m/z 364.0
(M+H)+

Example 206 : N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylthiomethyl)phenyl]urea EI-MS
m/z 394.0 (M-H)-

Example 207 : N-(2-Hydroxy-4-nitro phenyl)-N'-[2-(phenyloxymethyl)phenyl]urea EI-MS
25 m/z 378.0 (M-H)"

Example 208 : N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(phenylethyl)phenyl]urea EI-MS m/z
376.0 (M-H)-

Exampie 209 : N-(2-Hydroxy-4-nitrophenyI)-N'-[2-(4-trifluorophenyl)phenyl]urea EI-MS
m/z 4 16.0 (M-H)-

30 Example 210 : N-(2-Hydroxy-3-trifloromethylphenyl)-N'-(2-methoxyphenyl)urea EI-MS
m/z 327.3 (M+H)+

Example 211: N-(2-Hydroxy-4-nitrophenyl)-N'-(2-acetoxyphenyl)urea EI-MS m/z 332.0
(M+H)+

Example 212 : N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(2-cyanophenylthio)phenyl]urea EI-MS
35 m/z 407.0 (M+H) +

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Example 213 : N-C2-hydroxy-3-trifluoromethylphenyl)-N*-(2-chlorophenyl)urea m.p.
179.3°C

Example 214 : N-(2-Hydroxyethyl)-N'-(2-hydroxy-4-nitrophenyl)urea m.p. 168.2 - 168. 8°C
Example 215 : N-2-(benzyoxyphenyl)-N'-{2-hydroxy-4-nitrophenyl)urea m.p. 179.0 -
179.6°C

Example 216 : N-[2-(2-thienylsulfonylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea
m.p. 149.0 - 149.6°C

Example 217 : N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2,3-dichlorophenyl)urea
l H NMR (CD3OD): 8 9.92 (lH,s) 9.68 (lH,s) 9.58 (lH.s) 8.40 (lH,d) 8.14 (lH,dd) 8.00
(lH.d) 7.76-7.57 (6H,m) 7.38 (lH,dO 7.23 (lH,d)

Example 218 : N-(2-Benzenesulfonylamino-4-nitrophenyl)-N'-(2-bromophenyl)urea
NMR (CD3OD): 5 9.89 (lH.s) 9.51(lH,s) 9.35 (lH,s) 8.41(lH,d) 8.13(lH,dd) 7.87 (lH,d)

7.69-7.57 (6H,m) 7.40 (lH,t) 7.22 (lH,dd) 7.10 (lH,t)

Example 219 : N-(2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2-bromophenyl)urea
NMR (CD3OD): 8 9.58 (1H.S) 9.30 (lH,s) 9.14 (lH.s) 8.33 (lH,d) 8.13-8.05 (2H,m) 7.88

(lH.d) 7.69 (lH,d) 7.50 -7.30 (6H,m) 7.08 (lH.t) 4.61 (2H,s)

Example 220 : N-(2-Benzylsulfonylamino-4-nitrophenyl)-N'-(2,3dichlorophenyl)urea *H
NMR (CD3OD): 8 9.60 (lH.s) 9.42(lH,s) 9.40 (lH.s) 8.32 (lH.d) 8.15(lH,dd) 7.45-7.25

(7H,m) 4.62 (2H,s)

Example 221 : N-[2-(3-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea m.p.
185.4 - 186.2

Example 222 : N-[2-(4-Pyridylmethoxy)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea m.p.
189.3 - 189.7

Example 223 : N-[2-(Methoxycarbonylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea
m.p. 199.3 - 199.6

Example 224 : N-[2-(Methylsulfonylamino)-4-nitrophenyl]-N'-(2-bromophenyl)urea
Example 225 : N-[2-(Propylsulfonylamino)-4-nitrophenyl)-N'-(2-bromophenyl)urea
Example 226 : N-[2-(Propylsulfonylamino)-4-nitrophenyl]-N'-(2,3-
dichlorophenyl)urea

Example 227 : N-[[(2-acetamino-4-methyl-5-thiazolyl)sulfonylamino]-4-
nitrophenyl]-N'-(2,3dichlorophenyl)urea

Example 228 : N-[2-(3-Pyridinesulfonylamino)-4-nitrophenyl]-N'-(2,3-
dichlorophenyl)urea

Example 229 : N-[2-(3-Pyridinesulfonylamino)-4-nitrophenyl]-N , -(2-
bro mopheny 1) urea

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Example 230 : N-f2-(MethylsulfonyIamino)-4-nitrophenyl]-N'-(2,3-
dichlorophenyl)urea

Example 231 : N-(2-Hydroxyeth-l-yloxyphenyl)-N'-(2-hydroxy-4-nitrophenyl)urea
Example 232 : N-(2-Hydroxy-4-cyanophenyl)-N'-(2-benzylaminophenyl)urea m.p.: 108
109.4

Example 233 : N'-[2-(2-Pyridylmethoxy)phenyl]-N'-(2-Hydroxy-4-nitrophenyl)urea m.p
193.5-194.0

Example 234 : N-[2-(2-Methoxycarbonylbenzyloxyphenyl]-N-(2-hydroxy-4-
nitrophenyl)urea m.p. 177.2 - 178.0

Example 235 : N-[2-(2-Carboxybenzyloxy)phenyl)-N'-(2-hydroxy-4-nitrophenyI)urea m
164.1

Example 236 : N-[2-(Benzoylamino)phenyl]-N'-(2-hydroxy-4-nitrophenyl)urea m.p.
188.7- 189.3 ° C

The following compounds of Formula (I) may be prepared in accordance with
the examples and schemes as described above:
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(benzyloxy)phenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(2-pyridylmethyloxy)phenyl)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(3-pyridylmethyloxy)phenyI)urea
N-(2-Hydroxy-4-cyanophenyl)-N'-(2-(4-pyridylmethyloxy)phenyl)urea
N-(2-Hydroxy-4-trifIuoroacetophenone)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-trifluorosulfonylphenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2-bromophenyl)urea
N-(2-Hydroxy-4-trifluoroacetophenone)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-4-trifluorosulfonylphenyl)-N , -(2,3-dichlorophenyl)urea
N-(2-Hydroxy-3-bromo-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-3-chloro-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-3-trifluoromethyl-4-cyanophenyl)-N'-(2,3-dichlorophenyl)urea
N-(2-Hydroxy-4-cyanophenyl-3-carboxylic acid)-N'-(2,3-dichlorophenyl)urea

The following compounds of Formula (I) may be prepared in accordance with
the examples and schemes as described above, or may also be purchased commercially
from well recognized sources. For instance, from Aldrich Chemical Company:
N-(2-Hydroxy-4-nitrophenyl)-N'-phenylurea

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For instance, from the Alfred Bader Collection of Aldrich Chemical:
l-(2-Carboxyphenyl)-3-(3-fluorophenyl)urea
l-(2-Carboxyphenyl)-3-(3-chlorophenyl)urea

5

Available from Gallard Schlesinger Company and/or the Sigma Aldrich Library
of Rare Compounds:

l-(2-Carboxyphenyl)-3-(4-chlorophenyl)urea

1- (p-Anisyl)-3-(2-carboxyphenyl)urea Available from Gallard Schlisinger Company :
10 2-(3,4-Dichlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid

2- (4-Chlorophenylcarbonyldiimino)-5-trifluoromethylbenzoic acid
N-Phenyl-N'-(2-carboxyphenyl)urea

From Maybridge Chemical Company, Cambridge England:
15 l,l'-(4-Methyl-2-phenylene)bis[3-tolyl)]thiourea

N-(5-Chloro-2-hydroxy-4-nitrophenyl)-N'-phenylurea

The following compounds of Formula (I) may be prepared in accordance with
the examples and schemes as described above, or as indicated by their respective
20 citations in Chemical Abstracts:

l-(m-Anisyl)-3-(2-carboxyphneyl)urea
l-(o-Anisyl)-3-(2-carboxyphenyl)urea
l-(2-Carboxyphenyl)-3-(3,4-dichlorophenyl)urea
l-(2-Carboxyphenyl)-3-(2,4-dichlorophenyl)urea

25

METHOD OF TREATMENT

The compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib), (lie), and (HI),
or a pharmaceutical^ acceptable salt thereof can be used in the manufacture of a
medicament for the prophylactic or therapeutic treatment of any disease state in a

30 human, or other mammal, which is exacerbated or caused by excessive or unregulated
IL-8 cytokine production by such mammal's cell, such as but not limited to monocytes
and/or macrophages, or other chemokines which bind to the IL-8 a or b receptor, also
referred to as the type I or type II receptor.

For purposes herein, the compounds of Formula (I), (la), (lb), (Ic), (II, (Ha ),

35 (lib), (lie), and (III) all have the same dosages, and dosage formulations as that of
Formula (I) and are used interchangeably.

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Accordingly, the present invention provides a method of treating a chemokine
mediated disease, wherein the chemokine is one which binds to an EL-8 a or b receptor
and which method comprises administering an effective amount of a compound of
Formula (I) or a pharmaceutically acceptable salt thereof. In particular, the
5 chemokines ars IL-8, GROa, GROP, GROy or NAP-2.

The compounds of Formula (I) are administered in an amount sufficient to
inhibit cytokine function, in particular IL-8, GROa, GROP, GROy or NAP-2 , such that
they are biologically regulated down to normal levels of physiological function, or in

10 some case to subnormal levels, so as to ameliorate the disease state. Abnormal levels of
IL-8, GROa, GROP, GROy or NAP-2 for instance in the context of the present
invention, constitute: (i) levels of free EL-8 greater than or equal to 1 picogram per mL;
(ii) any cell associated EL-8, GROa, GROP, GROy or NAP-2 above normal
physiological levels; or (iii)the presence of EL-8, GROa, GROp, GROy or NAP-2

15 above basal levels in cells or tissues in which IL-8, GROa, GROP, GROy or NAP-
2respectively, is produced.

There are many disease states in which excessive or unregulated EL-8 production
is implicated in exacerbating and/or causing the disease. Chemokine mediated diseases

20 include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary
disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, stroke, septic shock, endotoxic shock, gram negative sepsis,
toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis,
thrombosis, graft vs. host reaction, alzheimers disease, allograft rejections, malaria,

25 restinosis, angiogenesis or undesired hematopoietic stem cells release.

These diseases are primarily characterized by massive neutrophil infiltration, T-
cell infiltration, or neovascular growth, and are associated with increased EL-8 GROa,
GROp, GROy or NAP-2 production which is responsible for the chemotaxis of

30 neutrophils into the inflammatory site or the directional growth of endothelial cells. In
contrast to other inflammatory cytokines (IL-1, TNF, and EL-6), EL-8 GROa, GROP,
GROy or NAP-2 has the unique property of promoting neutrophil chemotaxis, enzyme
release including but not limited to elastase release as well as superoxide production and
activation. The a-chemokines but particularly, GROa, GROP, GROy or NAP-2,

35 working through the EL-8 type I or II receptor can promote the neovascularization of
tumors by promoting the directional growth of endothelial cells. Therefore, the

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inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in
the neutrophil infiltration.

The compounds of Formula (I) are administered in an amount sufficient to
5 inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors,
such as evidenced by a reduction in neutrophil chemotaxis and activation. The
discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is based
upon the effects of the compounds of Formulas (I) in the in vitro receptor binding
assays which are described herein. The compounds of Formula (I) have been shown to
10 be dual inhibitors of both recombinant type I and type II IL-8 receptors. Preferably the
compounds are inhibitors of only one receptor, preferably Type H.

As used herein, the term "IL-8 mediated disease or disease state" refers to any
and all disease states in which EL-8, GROa, GROp, GROy or NAP-2 plays a role, either
15 by production of EL-8, GROa, GROP, GROy or NAP-2 themselves, or by IL-8 GROa,
GROP, GROy or NAP-2 causing another monokine to be released, such as but not
limited to IL-1, IL-6 or TNF. A disease state in which, for instance, IL-1 is a major
component, and whose production or action, is exacerbated or secreted in response to
IL-8, would therefore be considered a disease stated mediated by IL-8.

20

As used herein, the term "chemokine mediated disease or disease state" refers to
any and all disease states in which a chemokine which binds to an IL-8 a or b receptor
plays a role, such as but not limited to IL-8, GROa, GROp, GROy or NAP-2. This
would include a disease state in which, IL-8 plays a role, either by production of IL-8
25 itself, or by EL-8 causing another monokine to be released, such as but not limited to EL-
1, EL-6 or TNF. A disease state in which, for instance, EL- 1 is a major component, and
whose production or action, is exacerbated or secreted in response to EL-8, would
therefore be considered a disease stated mediated by EL-8.

30 As used herein, the term "cytokine" refers to any secreted polypeptide that

affects the functions of cells and is a molecule which modulates interactions between
cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but
is not limited to, monokines and lymphokines, regardless of which cells produce them.
For instance, a monokine is generally referred to as being produced and secreted by a

35 mononuclear cell, such as a macrophage and/or monocyte. Many other cells however
also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils,
endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes

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and B-lymphocytes. Lymphokines are generally referred to as being produced by
lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin- 1
(IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-
a) and Tumor Necrosis Factor beta (TNF-6).

As used herein, the term "chemokine" refers to any secreted polypeptide that
affects the functions of ceils and is a molecule which modulates interactions between
cells in the immune, inflammatory or hematopoietic response, similar to the term
"cytokine" above. A chemokine is primarily secreted through cell transmembranes and
causes chemotaxis and activation of specific white blood cells and leukocytes,
neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth
muscle cells. Examples of chemokines include, but are not limited to, IL-8 GROa,
GROp, GROy, NAP-2, IP-10, MlP-la, MlP-b, PF4, and MCP 1, 2, and 3.

In order to use a compound of Formula (I) or a pharmaceutically acceptable salt
thereof in therapy, it will normally be formulated into a pharmaceutical composition in
accordance with standard pharmaceutical practice. This invention, therefore, also
relates to a pharmaceutical composition comprising an effective, non-toxic amount of a
compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.

Compounds of Formula (I), pharmaceutically acceptable salts thereof and
pharmaceutical compositions incorporating such may conveniently be administered by
any of the routes conventionally used for drug administration, for instance, orally,
topically, parenterally or by inhalation. The compounds of Formula (I) may be
administered in conventional dosage forms prepared by combining a compound of
Formula (I) with standard pharmaceutical carriers according to conventional
procedures. The compounds of Formula (I) may also be administered in conventional
dosages in combination with a known, second therapeutically active compound. These
procedures may involve mixing, granulating and compressing or dissolving the
ingredients as appropriate to the desired preparation. It will be appreciated that the
form and character of the pharmaceutically acceptable character or diluent is dictated by
the amount of active ingredient with which it is to be combined, the route of
administration and other well-known variables. The carrier(s) must be "acceptable" in
the sense of being compatible with the other ingredients of the formulation and not
deleterious to the recipient thereof.

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The pharmaceutical carrier employed may be, for example, either a solid or
liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar,
pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid
carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or
5 diluent may include time delay material well known to the art, such as glyceryl mono-
stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid
carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in
10 powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier
will vary widely but preferably will be from about 25mg. to about lg. When a liquid
carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin
capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.

15 Compounds of Formula (I) may be administered topically, that is by non-

systemic administration. This includes the application of a compound of Formula (I)
externally to the epidermis or the buccal cavity and the instillation of such a compound
into the ear, eye and nose, such that the compound does not significantly enter the blood
stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal

20 and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid
preparations suitable for penetration through the skin to the site of inflammation such as
liniments, lotions, creams, ointments or pastes, and drops suitable for administration -to
25 the eye, ear or nose. The active ingredient may comprise, for topical administration,
from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation.
It may however comprise as much as 10% w/w but preferably will comprise less than
5% w/w, more preferably from 0. 1% to 1% w/w of the Formulation.

30 Lotions according to the present invention include those suitable for application

to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally
containing a bactericide and may be prepared by methods similar to those for the
preparation of drops. Lotions or liniments for application to the skin may also include
an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a

35 moisturizer such as glycerol or an oil such as castor oil or arachis oil.

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Creams, ointments or pastes according to the present invention are semi-solid
formulations of the active ingredient for external application. They may be made by
mixing the active ingredient in finely-divided or powdered form, alone or in solution or
suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with

5 a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or
liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin
such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty
acid such as steric or oleic acid together with an alcohol such as propylene glycol or a
macrogel. The formulation may incorporate any suitable surface active agent such as an

10 anionic, cationic or non-ionic surfactant such as a sorbitan ester or a poly oxye thy lene
derivative thereof. Suspending agents such as natural gums, cellulose derivatives or
inorganic materials such as silicaceous silicas, and other ingredients such as lanolin,
may also be included.

15 Drops according to the present invention may comprise sterile aqueous or oily

solutions or suspensions and may be prepared by dissolving the active ingredient in a
suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other
suitable preservative, and preferably including a surface active agent. The resulting
solution may then be clarified by filtration, transferred to a suitable container which is

20 then sealed and sterilized by autoclaving or maintaining at 98- 100 °C. for half an hour.
Alternatively, the solution may be sterilized by filtration and transferred to the container
by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for
inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium
chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the

25 preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

Compounds of formula (I) may be administered parenterally, that is by
intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or
intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral
30 administration are generally preferred. Appropriate dosage forms for such

administration may be prepared by conventional techniques. Compounds of Formula
(I) may also be administered by inhalation, that is by intranasal and oral inhalation
administration. Appropriate dosage forms for such administration, such as an aerosol
formulation or a metered dose inhaler, may be prepared by conventional techniques.

For all methods of use disclosed herein for the compounds of Formula (I), the
daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total

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body weight. The daily parenteral dosage regimen about 0.001 to about 80 mg/kg of
total body weight. The daily topical dosage regimen will preferably be from 0. 1 mg to
150 mg, administered one to four, preferably two or three times daily. The daily
inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg
5 per day. It will also be recognized by one of skill in the art that the optimal quantity
and spacing of individual dosages of a compound of Formula (I) or a pharmaceutical^
acceptable salt thereof will be determined by the nature and extent of the condition
being treated, the form, route and site of administration, and the particular patient being
treated, and that such optimums can be determined by conventional techniques. It will
10 also be appreciated by one of skill in the art that the optimal course of treatment, i.e.,

the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt
thereof given per day for a defined number of days, can be ascertained by those skilled
in the art using conventional course of treatment determination tests.

15 The invention will now be described by reference to the following biological

examples which are merely illustrative and are not to be construed as a limitation of the
scope of the present invention.

BIOLOGICAL EXAMPLES

20 The IL-8, and Gro-a chemokine inhibitiory effects of compounds of the present

invention were determined by the following in vitro assay:
Receptor Binding Assays:

[ 125 I] IL-8 (human recombinant) was obtained from Amersham Corp.,
Arlington Heights, DL, with specific activity 2000 Ci/mmol. Gro-a was obtained from

25 NEN- New England Nuclear. All other chemicals were of analytical grade. High levels
of recombinant human IL-8 type a and b receptors were individually expressed in
Chinese hamster ovary cells as described previously (Holmes, ex al.. Science, 1991, 253,
1278). The Chinese hamster ovary membranes were homogenized according to a
previously described protocol (Haour, et al., J Biol Chem., 249 pp 2195-2205 (1974)).

30 Except that the homogenization buffer was changed to lOmM Tris-HCL, ImM MgS04,
0.5mM EDTA (ethylene-diaminetetra-acetic acid), ImMPMSF (a-toluenesulphonyl
fluoride), 0.5 mg/L Leupeptin, pH 7.5. Membrane protein concentration was
determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard.
All assays were performed in a 96-well micro plate format. Each reaction mixture

35 contained 125 I IL-8 (0.25 nM) or 125 I Gro-a and 0.5 ug/mL of IL-8Ra or 1 .0 ug/mL of
EL-8Rb membranes in 20 mM Bis-Trispropane and 0.4 mM Tris HC1 buffers, pH 8.0,
containing 1.2 mM MgS04, 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS. In

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addition, drug or compound of interest was added which had been pre-dissolved in
DMSO so as to reach a final concentration of between O.OlnM and 100 uM. The assay
was initiated by addition of 125 I-IL-8. After 1 hour at room temperature the plate was
harvested using a Tomtec 96- well harvester onto a glass fiber filtermat blocked with 1%
5 polyethylenimine/0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCl, 1
mM MgS04, 0.5 mM EDTA, 0.03 % CHAPS, pH 7.4. The filter was then dried and

counted on the Betaplate liquid scintillation counter. The recombinant EL-8 Ra, or Type
I, receptor is also referred to herein as the non-permissive receptor and the recombinant
IL-8 Rb, or Type II, receptor is referred to as the permissive receptor.

10

All of the exemplified compounds of Formulas (I) to (III) noted herein in the
Synthetic Chemistry Section, of Examples 1 to 222 plus the additional purchased
compounds demonstrated an IC50 from about 45 to about <1 ug/mL in the permissive

models for EL-8 receptor inhibition. All of these compounds were also found to be
15 inhibitors of Gro-a binding at about the same level. The compound l-(2-

Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea was found to be active at about 75
ug/mL.

The following compounds, generally tested at levels of up to 45 Ug/mL were
20 found to not demonstrate levels of IL-8 receptor antagonism within the criteria set forth
above at the dosage levels tested. These compounds are:
l-f4-Chloro-alpha,alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenyl)thio]-5-
chlorophenyl urea

l-(6-Chloro-alpha,alpha,alpha-trifluoro-3-tolyl)-3-[2-(4-chlorophenoxy)-5-
25 chlorophenyl]urea

l-(2-Mercaptophenyl)-3-phenyl-2-thiourea

l-(2-Hydroxyphenyl)-3-phenyl-2-thiourea

3,3'-(Carbonothioyldiimino)bist4-hydroxybenzoic acid]

m,m'-(l,3-thioureylene)di(4-hydroxybenzoic acid)
30 1 -(2-Tolyl)-3-(3-chloro-6-hydroxyphenyl)-2-thiourea

l-[(2-Hydroxy-4-aminophenyl)]-(3-phenyl)-urea

N-(2-Carboxy-4-trifluromethylphenyl)-N'-(3-chlorophenyl)urea

N-(2-Carboxyphenyl)-N'-(2,5-dichlorophenyl)urea

1- (2-Carboxyphenyl)-3-(2-Chloro-5-trifluoromethylphenyl)urea

35 2-[2-[3-(4-Bromophenyl)ureido]-4-trifluoromethylphenoxy]benzoic acid;

2- [2-[3-(4-Chlorophcnyl)ureido]phenoxy]benozic acid
2-[2-[3-(4-Chloro3-(trifluromethyl)phenyl)ureido]phenoxy]benozic acid

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N- (2-Hydroxyphenyl) -N'-phenyl urea N-[2-Hydroxy-5-(methoxycarbonyl)phenyl]-N'-
phenylurea

N-[4-Carboxy-2-hydroxyphenyl]-n'-phenylurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(4-nitrophenyl)urea;

l-(2-Carboxyphenyl)-3-(2,6-xylyl)urea

l-(6-Carboxy-2,4-dichlorophenyl)-3-(2,4,6-trichlorophenyl)urea

l-(2-Carboxyphenyl)-3-(2,5-dimethoxyphenyl)urea

l-(2-Carboxyphenyl)-3-(2-methylphenyl)urea

l-[(2-Hydroxyphenyl)-3-(2-methyl)-5-nitrophenyl]urea

l-(2,5-Dichiorophenyl)-3-(2-hydroxy-4-nitrophenyl)urea

l-(2-Carboxyphenyl)-3-(4-chloro-2-methylphenyl)urea

N-(2-phenylsulfonylaminophenyl-N'-phenylurea

N-(2-Hydroxy-4-nitrophenyl)-N'-(4-ethoxycarbonylphenyl)urea

N-(2-Hydroxy-4-nkrophenyl)-N'-(2-ethoxycarbonylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(3-ethoxycarbonylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(4-phenylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(4-phenoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(4-propylphenyl)urea

N-(4-Trifluromethyl-2-(4-nitrobenzcnesulfonyl)amino]-N'-phenylurea

N-(3-Carboxyphenyl)-N'-2-hydroxy-4-nitrophenyl)urea

N-(4-Trifluromethyl-2-(methylsulfonyl)amino]-N'-phenylurea

N-(2-Hydroxy-4-nitrophenyl)-N'-[2-(isopropyl)phenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2,6-dimethylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-fluoro-5-nitrophenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-chloro-5-trifluromethylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-4-nitrophenyl)urea

N-(2-Hydroxy-l-napthyl)-N'-(2-phenylphenyl)urea

N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-bromophenyl)urea

N-(2-hydroxy 3,4 dichlorophenyl )-N'-(4-phenylphenyl)urca
N-{2-hydroxy-3-naphthyl)-N'-(2-methoxyphenyl)urea

N-(2-hydroxy-3-naphthyl)-N'-(2-phenylphenyl)urea

N-(2-Hydroxy-3-naphthyl)-N'-(4-methoxyphenyl)urea

N-(2-Hydroxy-3-naphthyl)-N'-(3-trifluoromethylphenyl)urea

N-(2-Hydroxy-3-naphthyl)-N'-(4-phenylphenyl)urea

N-[2-(2-Carboxyphenylsulfonylamino)phenyl]-N , -(2-bromophenyl)urea

N-(2-Hydroxy-3-phenylphenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-3-phenylphenyl)-N'-(4-methoxyphenyl)urea

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N-(2-Hydroxy-3-phenylphenyl)-N'-(3-triflouromethylphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-3-phenylphenyl)-N'-(4-phenylphenyl)urea
N-[2-[(2,5-Dichlorothien3-yl)sulfonylanuno]phenyl]-N'-(2-bromophenyl)urea

5 N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2,4 dimethoxyphenyl)urea

N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-chloro-5-trifloromethylphenyl)urea
N-(2-Hydroxy-3-naphthyl)-N'-(2,4 dimethoxyphenyl)urea
N-(2-Hydroxy-3-naphthyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-(2-Hydroxy-3 phenylphenyl)-N'-(2,4-dimethoxyphenyl)urea

1 0 N- (2-Hydroxy-4- isopropy lpheny 1 )-N'-(2 ,4-dimethoxypheny l)urea

N-(2-Hydroxy-3-phenylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-(2-Hydroxy-5-nitrophenyl)-N'-(2,4-dimethoxyphenyl)urea
N-(2-Hydroxy-5-nitrophenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-(2-Hydroxy-3-cyanophenyl)-N'-(4-methoxyphenyl)urea

1 5 N-(2-Hydroxy-3-cyanophenyl)-N'-(4-phcnylphenyl)urea

N-(2-Hydroxy-3-cyanophenyI)-N'-(2,4 dimethoxyphenyl)urea
N-<2-Hydroxy-3-cyanophenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-(2-Hydroxy- 5-phenylphenyl)-N'-(2-methoxyphenyl)urea
N- (2-Hy droxy- 5-pheny lphenyl)-N'-(4-methoxyphenyl)urea

20 N-(2-Hydroxy- 5-phenylphenyl)-N'-(3-trifluoromethylphenyl)urea
N-(2-Hydroxy- 5-phenylphenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-5-phenylphenyl)-N'-(4-phenylphenyl)urea
N-(2-Hydroxy-5-phenylphenyl)-N'-(2,3-dichlorophcnyl)urea
N-(2-Hydroxy-5-phenylphenyl)-N'-(2,4-dimethoxyphenyl)urea

25 N-(2-Hydroxy-5-phenylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(4-methoxyphenyl)urea
N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(3-trifluoromethylphenyl)urea
N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-phenylphenyl)urea
N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(4-phenylphenyl)urea

30 N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2,4-dimethoxyphenyl)urea

N-(2-Hydroxy-5-ethylsulfonylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2,4 dimethoxyphenyl] urea
N-[2-Hydroxy-3,4-dichlorophenyl]-N'-[2-chloro-5-trifluoromethylphenyl] urea
N-[2-Hydroxy-3-naphthyl]-N'-[3-trifluoromethylphenyl] urea

35

Chemotaxis Assay :

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The in vitro inhibitory properties of these compounds were determined in the
neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol I,
Suppl 1, Unit 6.12.3., whose disclosure is incorporated herein by reference in its
entirety. Neutrophils where isolated from human blood as described in Current

5 Protocols in Immunology Vol I, Suppl 1 Unit 7.23. 1, whose disclosure is incorporated
herein by reference in its entirety. The chemoattractants IL-8, GRO-a, GRO-b, GRO-g
and NAP-2 where placed in the bottom chamber of a 48 multiwell chamber (Neuro
Probe, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two
chambers where separated by a 5um polycarbonate filter. When compounds of this

10 invention were tested, they where mixed with the cells (0.001 - 1000 nM) just prior to
the addition of the cells to the upper chamber. Incubation was allowed to proceed for
between about 45 and 90 min at about 37°C in a humidified incubator with 5% CO2.
At the end of the incubation period, the polycarbonate membrane was removed and the
top side washed, the membrane was then stained using the Diff Quick staining protocol

15 (Baxter Products, McGaw Park, IL, USA). Cell which had chemotaxed to the

chemokine were visually counted using a microscope. Generally, four fields where
counted for each sample, these number where averaged to give the average number of
cells which had migrated. Each sample was tested in triplicate and each compound
repeated at least four times. To certain cells (positive control cells) no compound was

20 added, these cells represent the maximum chemotactic response of the cells. In the

case where a negative control (unstimulated) was desired, no chemokine was added to
the bottom chamber. The difference between the positive control and the negative
control represents the chemotactic activity of the cells.

25 Elastase Re lease Assav:

The compounds of this invention where tested for their ability to prevent
Elastase release from human neutrophils. Neutrophils where isolated from human blood
as described in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1. PMNs
0.88 x 10 6 cells suspended in Ringer's Solution (NaCl 118, KC1 4.56, NaHC03 25,
30 KH2P04 1.03, Glucose 1 1.1, HEPES 5 mM, pH 7.4) where placed in each well of a 96
well plate in a volume of 50 ul. To this plate was added the test compound (0.001 -
1000 nM) in a volume of 50 ul, Cytochalasin B in a volume of 50 ul (20ug/ml) and
Ringers buffer in a volume of 50 ul. These cells where allowed to warm (37 °C, 5%
C02, 95% RH) for 5 min before IL-8, GROa, GROb, GROg or NAP-2 at a final
35 concentration of 0.01 - 1000 nM was added. The reaction was allowed to proceed for
45 min before the 96 well plate was centrifuged (800 xg 5 min) and 100 ul of the
supernatant removed. This suppernatant was added to a second 96 well plate followed

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by an artificial elastase substrate (MeOSuc- Ala- Ala-Pro- Val-AMC, Nova Biochem, La
Jolla, CA) to a final concentration of 6 ug/ml dissolved in phosphate buffered saline.
Immediately, the plate was placed in a fluorescent 96 well plate reader (Cytofluor 2350,
Millipore, Bedford, MA) and data collected at 3 min intervals according to the method
5 of Nakajima et al J. Biol Chem 25.4 4027 (1979). The amount of Elastase released from
the PMNs was calculated by measuring the rate of MeOSuc- Ala-Ala-Pro-Val-AMC
degradation.

The above description fully discloses the invention including preferred
10 embodiments thereof. Modifications and improvements of the embodiments

specifically disclosed herein are within the scope of the following claims. Without
further elaboration, it is believed that one skilled in the are can, using the preceding
description, utilize the present invention to its fullest extent. Therefore the Examples
herein are to be construed as merely illustrative and not a limitation of the scope of the
15 present invention in any way. The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows.

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1 . A method of treating a chemokine mediated disease state, wherein the
chemokine binds to an IL-8 a or b receptor in a mammal, which comprises
administering to said mammal an effective amount of a compound of the formula:

wherein

X is oxygen or sulfur;

R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
Ci-ioalkoxy; azide; S(0)tR4; (CRgRg)q S(0)tR4; hydroxy; hydroxy substituted
Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1.4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;
heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10
alkenyl; (CRgR 8 )q NR4R5; (CR 8 R 8 )q C(0)NR4Rs; C2-10 alkenyl C(0)NR4Rs;
(CR 8 R 8 )q C(O)NR4Rl0; S(0)3H; S(0)3R 8 ; (CR 8 R 8 )q C(0)Rn; C2-10 alkenyl
C(0)Ri 1; C2-10 alkenyl C(0)ORi 1; (CR 8 R 8 )q C(0)ORi 1; (CR 8 R 8 )q OC(0)Ri i ;
(CR 8 Rg)qNR4C(0)Ri 1; (CRgRg)q C(NR4)NR 4 R 5 ; (CRgRg)q NR4C(NR 5 )R U , '
(CR 8 Rg)q NHS(0) 2 Ri3; (CRgRg)q S(0) 2 NR 4 R 5 , or two Ri moieties together may
form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted Ci .4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci_4alkyl, heterocyclic, heterocyclic
C1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form
a 5 to 7 member ring which may optionally comprise an additional heteroatom
selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci- 10 alkyl; Ci-io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)qS(0) t R4,
(CRgRg)qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Ci-4 alkyl;
aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;

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heteroaryl C1-4 alkyloxy; heteroaryl C2-10 aikenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 aikenyl; (CR 8 R 8 )qNR4R5; C2-10 aikenyl
CCO)NR4R5; (CR 8 Rg)qC(0)NR4R5; (CR 8 R8)q C(O)NR4Rl0; S(0)3R8;
(CR 8 R 8 )qC(0)Rn; C2-10 alkenylC(0)Ri 1; (CR 8 R 8 )qC(0)ORi 1;
5 C2-10alkenylC(O)ORi 1; (CR 8 R 8 )qOC(0)Ri 1; (CR 8 R 8 )qNR4C(0)Ri l;

(CR 8 R 8 )qNHS(0) 2 Rb; (CRgR 8 )qS(0) 2 NR 4 R5; (CR 8 R 8 )qC(NR4)NR 4 R 5 ;
(CR 8 R 8 )q NR4C(NR5)Ri 1; or two Y moieties together may form 0-(CH2)sO- or a
5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,
heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally
10 substituted;

q is 0 or an integer having a value of 1 to 10;

m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a C1-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
15 may optionally contain an additional heteroatom which heteroatom is selected from

oxygen, nitrogen or sulfur;
R 8 is hydrogen or Ci-4 alkyl;
RlO is Ci-10 alkyl C(0)2R8;

Rl 1 is hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl,
20 optionally substituted aryl C i-4alkyl, optionally substituted heteroaryl, optionally

substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC 1 - 4 alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted

arylalkyl;

25 R13 is suitably Ci-4 alkyl, aryl, aryl Ci- 4 alkyl, heteroaryl, heteroarylCi-4alkyl,
heterocyclic, or heterocyclicC i-4alkyl;
R b is NR6R7, alkyl, aryl, aryl C 1.4 alkyl, aryl C2-4 aikenyl, heteroaryl, heteroaryl
Ci_4 alkyl, heteroarylC2_4 aikenyl, heterocyclic, heterocyclic C1.4 alkyl,
heterocyclic C2-4 aikenyl, or camphor, all of which groups may be optionally

30 substituted;

or a pharmaceutical^ acceptably salt thereof.

2. The method according to Claim 1 wherein the ionizable hydrogen has a pKa of 3
to 10.

35

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3. The method according to Claim 2 wherein R is hydroxy, carboxylic acid, thiol, -
SR2 -OR2, -NH-aO)R a , -CfO)NR6R7- -NHS(0)2Rb* -S(0)2NHRc, NHC(X)NHRb,
or tetrazolyl;

wherein R2 is a substituted aryl, heteroaryl, or heterocyclic moiety which ring
has the functional moiety providing the ionizable hydrogen having a pKa of 10 or less;

R$ and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7
together with the nitrogen to which they are attached form a 5 to 7 member ring which
ring may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;

R a is an alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroaryl Ci_4alkyl,
heterocyclic, or a heterocyclic Ci-4alkyl moiety, all of which may be optionally
substituted;

Rb is a NR6R7, alkyl, aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl,
heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Ci-4alkyl,
heterocyclic C2-4alkenyl moiety, camphor, all of which may be optionally substituted
one to three times independently by halogen; nitro; cyano, halosubstituted C 1-4 alkyl;
C1-4 alkyl; C1-4 alkoxy; Cl-4 amino, NRoC(0)R a ; C(0)NR6R7. S(0)3H, or
S(0) m -R a (wherein m' is 0, 1, or 2) or C(0)OCi_4 alkyl;

R9 is hydrogen or a C1-4 alkyl;

Rc is alkyl, aryl, arylC 1 _4alkyl, arylC2-4alkenyl, heteroaryl,
heteroarylCi-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic Ci-4alkyl, or a
heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three
times independently by halogen, nitro.cyano, halosubstituted Ci .4 alkyl, Ci-4 alkyl,
C1-4 alkoxy, Cl-4 amino , NRoC(0)R a , C(0)NR6R7, S(0)3H, or C(0)OCl-4 alkyl.

4. The method according to Claim 3 wherein the R2 is optionally substituted one to
three times by halogen, nitro, halosubstituted Ci-io alkyl, Ci-10 alkyl, Ci-io alkoxy,
hydroxy, SH, -C(0)NR6R7, -NH-C(0)R a , -NHS(0)Rb, S(0)NR6R7, C(0)OR8, or a
tetrazolyl ring.

5. The method according to Claim 3 wherein R is OH, -NHS(0)2Rb or C(0)OH.

6. The method according to Claim 1 wherein Ri is halogen, cyano, nitro, CF3,
C(0)NR4R5, alkenyl C(0)NR4R5, C(O) R4RIO, alkenyl C(0)ORi2, heteroaryl,
heteroarylalkyl , heteroaryl alkenyl, or S(0)NR4R5.

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7. The method according to Claim 1 wherein Y is halogen, Ci-4 alkoxy, optionally
substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4R5.
thioCi-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4alkyl,

hydroxy alkyl.

5

8. The method according to Claim 1 wherein R is OH, SH, or NHS(0) s Rb and Ri
is substituted in the 3-position, the 4- position or di substituted in the 3,4- position by an
electron withdrawing moiety.

10 9. The compound according to Claims I or 8 wherein Y is mono-substituted in the
2'-position or 3'- position, or is disubstituted in the 2'- or 3'- position of a monocyclic
ring.

10. The compound according to Claims 1, 8 or 9 wherein n amd m are each equal to
15 1 or more.

1 1. The method according to Claim 1 wherein R is a carboxylic acid, and Ri is
hydrogen, or Ri is substituted in the 4-position.

20 12. The method according to Claim 1 wherein the mammal is afflicted with a
chemokine mediated disease selected from psoriasis, or atopic dermatitis, asthma,
chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis,
inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic
shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal

25 reperfusion injury, glomerulo-nephritis, or thrombosis, alzheimers disease, graft vs. host
reaction, or allograft rejections.

13. The method according to Claim 1 wherein the compound, or a pharmaceutically

accepatable salt is:
30 N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methylthiophenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-dichlorophenyl)urea
35 N-(2-Hydroxy 4-nitro phenyl) N'-(2-chloro phenyl) urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2,3-methylenedioxyphenyl)urea

N-(2-Hydroxy-4-nitrophenyl)-N'-(2-methoxy-3-chlorophenyl)urea

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N-(2-hydroxy 4-nitro phenyl) N'-(2-phenyloxy phenyl) urea
N-(3-Chloro-2-hydroxyphenyl)-N'-(bromophenyl)urea

N-(2-Hydroxy-3-glycinemethylestercarbonylphenyl)-N'-(2-bromophenyl)urea

N-(3-Nitro-2-hydroxyphenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2-bromophenyl)urea

N-(3-Cyano-2-hydroxyphenyl)-N'-(2-bromophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-phenylphenyl)urea

N-(2-Hydorxy-4-cyanophenyl-N'-(2,3-dichlorophenyl)urea

N-(2-Hydroxy-4-cyanophenyl)-N'-(2-methylphenyl)urea

N-(2-Hydroxy-3-cyano-4-methylphenyl)-N'-(2-bromophenyl)urea

N_(4.Cyano-2-hydroxyphenyl)-N'-(2-trifluoromethylphenyl)urea

N-(3-Trifluoromethyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea

N-(3-Phenylaminocarbonyl-2-hydroxyphenyl)-N'-(2-bromophenyl)urea

N-(2-hydroxy 4-nitro phenyl) N'-(2-iodo phenyl) urea

N-(2-hydroxy 4-nitro phenyl) N'(2-bromo phenyl) thiourea

N-(2-phenylsulfonamido)-4-cyanophenyl-N'(2-bromo phenyl)urea

(E)-N-[3-[(2-Aminocarbonyl)ethenyl]-2-hydroxyphenyl]-N'-(2-bromophenyl)urea

N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-methoxyphenyl)urea

N-(2-Hydroxy,3,4-dichlorophenyl)-N'-(2-phenylphenyl)urea

N-(2-Hydroxy-3,4-dichlorophenyl)-N'-(2,3-dichlorophenyl)urea

N-(2-Hydroxy-5-nitrophenyl)-N'-(2,3-dichlorophenyl)urea; or

N-(2-Hydroxy-3-cyanophenyl)-N'-(2,3 dichlorophenyl)urea.

14. A compound of the formula::

X is oxygen or sulfur;

R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
Ci-ioalkoxy; azide; S(0) t R4; (CRgRg)q S(0)tR4; hydroxy; hydroxy substituted
Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl C1.4 alkyloxy;

(ID

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heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;
heterocyclic, heterocyclic C i-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10
alkenyl; (CRgRg)q NR4R5; (CR 8 Rg)q C(0)NR4R5; C2-10 alkenyl C(0)NR4R5;
(CR 8 R 8 )q C(O)NR4Rl0; S(0)3R8; (CR 8 R 8 )q C(0)Rn; C2-10 alkenyl C(0)Ri l;

5 C2-10 alkenyl C(0)ORi 1; (CR 8 Rg)q C(0)ORl 1; (CRgRg)q OC(0)Rl l ;

(CRgR 8 )qNR4C(0)Rl 1; (CRgR 8 )q C(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R!
(CR 8 R 8 )q NHS(0) 2 Ri3; (CRgRg)q S(0) 2 NR4R5, or two R\ moieties together may
form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;

10 t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci- 4 alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic,

15 heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are

attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S;
Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CRgRg)qS(0) t R4,

20 (CRgRg)qOR4; hydroxy; hydroxy substituted C 1 - 4 alkyl; aryl; aryl C 1-4 alkyl;

aryloxy; arylQ-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl Ci-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CRgRg)qNR4R5; C2-10 alkenyl
C(0)NR4R5; (CRgR 8 )qC(0)NR4R5; (CR 8 Rg)q C(O)NR4Rl0; S(0)3R8;

25 (CRgRg)qC(0)Rl 1; C2-10 alkenylC(0)R 1 1; (CR 8 Rg)qC(0)ORi 1;

C2-10alkenylC(O)ORi 1; (CRgRg)qOC(O) R\ 1; (CRgRg)qNR4C(0)Ri 1;
(CRgRg)q NHS(0) 2 Rb; (CRgRg)q S(0) 2 NR4R 5 ; (CR 8 Rg)qC(NR4)NR4R 5 ;
(CRgRg)q NR4C(NR5)Ri \; or two Y moieties together may form 0-(CH 2 ) s O- or a
5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,

30 heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally

substituted;
q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;

35 R6 and R7 are independently hydrogen or a Ci- 4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring

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may optionally contain an additional heteroatom which heteroatom is selected from

oxygen, nitrogen or sulfur;
R.8 is hydrogen or C 1.4 alkyl;
RlO isCi-ioalkyl C(0)2R8;
5 Ri 1 is hydrogen, optionally substituted C1-4 alkyl, optionally substituted aryl,

optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally

substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally

substituted heterocyclicC i-4alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted
10 arylalkyl;

Rl3 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl,

heterocyclic, or heterocyclicC i-4alkyl;
R b is NR 6 R 7> ^^y 1 - ary 1 ' ar y' c l-4 ^kyl, aryl C2.4 alkenyl, heteroaryl, heteroaryl

C1.4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Ci_ 4 alkyl,
15 heterocyclic C2.4 alkenyl, or camphor, all of which groups may be optionally

substituted;
E is optionally selected from

the asterix * denoting point of attachment of the ring, with at least one E being present;
20 or a pharmaceutical^ acceptably salt thereof.

15. A pharmaceutical composition comprising a compound according to Claim 14
and a pharmaceutically acceptable carrier or diluent.

25 16. A method of treating a chemokine mediated disease state, wherein the
chemokine binds to an IL-8 a or b receptor in a mammal, which comprises
administering to said mammal an effective amount of a compound of the formula
according to Claim 14.

30 17. A compound of the formula:

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wherein

X is oxygen or sulfur;

R is any functional moiety having an ionizable hydrogen and a pKa of 10 or less;
5 Ri is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
Ci-ioalkoxy; azide; S(0)tR4; (CRgRg)q S(0)tR4; hydroxy; hydroxy substituted
Ci-4alkyl; aryl; aryl C1-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl C1-4 alkyloxy;
10 heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi_4alkyloxy; heterocyclicC2-10

alkenyl; (CR 8 R 8 )q NR4R5; (CR 8 R 8 )q C(0)NR4R5; C2-10 alkenyl C(0)NR4R5;
(CR 8 R 8 )q C(O)NR4Rl0; S(0)3R8; (CR 8 R 8 )q C(0)Rn; C2-10 alkenyl C(0)Rn;
C2-10 alkenyl C(0)ORi 1; (CR 8 R 8 )q C(0)ORl 1; (CRgR 8 )q OC(0)Ri 1 ;
(CR 8 R 8 )qNR4C(0)Ri 1; (CR 8 R 8 )q C(NR 4 )NR4R 5 ; (CR 8 R 8 )q NR^NRs^ 1?
15 (CR 8 R 8 )q NHS(0)2Rb; (CR 8 R 8 )q S(0)2NR4R5, or two Ri moieties together may

form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
q is 0 or an integer having a value of 1 to 10;
t is 0, or an integer having a value of 1 or 2;
20 s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic,
heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are
25 attached form a 5 to 7 member ring which may optionally comprise an additional

heteroatom selected from O/N/S;
Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR 8 R 8 )qS(0) t R4,
(CR 8 R 8 )qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl Ci-4 alkyl;
30 aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;

heteroaryl C1-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CR 8 Rg )qNR4R5 ; C2-10 alkenyl

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CfO)NR4R5; (CR 8 R 8 )qC(0)NR4R5; (CR 8 Rg)q C(O)NR4Rl0; S(0)3R8;

(CR 8 Rg)qC(0)R 1 1 ; C2- 1 0 alkenylC(0)R 1 1 ; (CR 8 R 8 )qC(0)OR 1 1 ;

C2-i0alkenylC(O)ORn; (CR 8 R 8 )qOC(0) Rn; (CR 8 R 8 )qNR4C(0)Rn;

(CR 8 R 8 )q NHS(0) 2 Rb; (CR 8 R 8 )q S(0)2NR 4 R 5 ; (CR 8 R 8 )qC(NR4)NR4R 5 ;

(CR 8 R 8 )q NR4C(NR5)Ri i; or two Y moieties together may form 0-(CH2)sO- or a

5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,

heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally

substituted;
n is an integer having a value of 1 to 3;
m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a C 1-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;

Rg is hydrogen or C 1-4 alkyl;

RlO is Ci-10 alkyl C(0)2R8;

Rl 1 is hydrogen, optionally substituted C\-4 alkyl, optionally substituted aryl,

optionally substituted aryl Cl-4alkyl, optionally substituted heteroaryl, optionally
substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC 1 -4alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted
arylalkyl;

Rl3 is suitably Ci- 4 alkyl, aryl, aryl Ci- 4 alkyl, heteroaryl, heteroarylCi-4alkyl,

heterocyclic, or heterocyclicC l-4alkyl;
Rb is NR$R7, alkyl, aryl, aryl C1.4 alkyl, aryl C2-4 alkenyl, heteroaryl, heteroaryl
Ci_4 alkyl, heteroarylC 2 -4 alkenyl, heterocyclic, heterocyclic Cj_4 alkyl,
heterocyclic C2.4 alkenyl, or camphor, all of which groups may be optionally

substituted;
E is optionally selected from

the asterix * denoting point of attachment of the ring;
or a pharmaceutically acceptably salt thereof.

- 132 -

WO 97/29743

PCT7US96/13632

18. A pharmaceutical composition comprising a compound according to Claim 17
and a pharmaceutically acceptable carrier or diluent.

19. A method of treating a chemokine mediated disease state, wherein the
chemokine binds to an IL-8 a or b receptor in a mammal, which comprises
administering to said mammal an effective amount of a compound of the formula
according to Claim 17.

10 20. A compound of the formula:

NHS(0) 2 Rb

X is oxygen or sulfur;

15 R a is an alkyl, aryl, arylCi-4alkyl, heteroaryl, heteroaryl Cl-4alkyl, heterocyclic, or a
heterocyclic Ci-4alkyl moiety, all of which may be optionally substituted;
Rb is a NR6R7, alkyl, aryl, arylCi-4alkyl, aryl C2-4alkenyl, heteroaryl,

heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclic
Ci-4alkyl, or a heterocyclic C2-4alkenyl moiety, camphor, all of which may be

20 optionally substituted one to three times independently by halogen; nitro;

halosubstituted C1-4 alkyl; Ci-4 alkyl; C1-4 alkoxy; NR9C(0)R a ; S(0) m -R a ,

C(0)NR6R7. S(0)3H, or C(0)OCl-4 alkyl;
R6 and R7 are independently hydrogen, or a Ci-4 alkyl group, or R6 and R7 together
with the nitrogen to which they are attached form a 5 to 7 member ring which ring
25 may optionally contain an additional heteroatom which heteroatom is selected from

oxygen, nitrogen or sulfur, which ring may be optionally substitued;
R9 is hydrogen or a Ci-4 alkyl, preferably hydrogen;

Rl is independently selected from hydrogen; halogen; nitro; cyano; Ci-10 alkyl;
halosubstituted C 1-10 alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted
30 Ci-ioalkoxy; azide; S(0) t R4; (CRgR8>q S(0) t R4; hydroxy; hydroxy substituted

Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci-4 alkyloxy;
heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;
heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10
alkenyl; (CR 8 Rg)q NR4R5; (CRgRg)q C(0)NR4R5; C2-10 alkenyl C(0)NR4R5;

- 133 -

WO 97/29743

PCTYUS96/13632

(CR 8 R 8 )q C(O)NR4Rl0; S(0)3R 8 ; (CR 8 Rg)q C(0)Ri l ; C2-10 alkenyl C(0)Rn;
C2-10 alkenyl C(0)ORi l ; (CR 8 R 8 )q C(0)ORn; (CR 8 R 8 )q OC(0)Rn ;
fCR 8 R 8 )qNR4C(0)Rl i; (CR 8 R 8 )q C(NR 4 )NR 4 R 5 ; (CR 8 R 8 )q NR 4 C(NR 5 )R 1 lt
(CR 8 R 8 )q NHS(0) 2 Ri3; (CR 8 R 8 )q S(0) 2 NR 4 R 5 , or two Ri moieties together may
form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,
arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;

t is 0, or an integer having a value of 1 or 2;

s is an integer having a value of 1 to 3;

R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic,
heterocyclicC 1-4 alkyl, or R4 and R5 together with the nitrogen to which they are
attached form a 5 to 7 member ring which may optionally comprise an additional
heteroatom selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10
alkenyl; Ci-io alkoxy; halosubstituted Ci_io alkoxy; azide; (CRgR 8 )qS(0) t R4,
(CRgRg)qOR4; hydroxy; hydroxy substituted Ci_4alkyl; aryl; aryl Ci-4 alkyl;
aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;
heteroaryl Ci-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CRgRg)qNR4R5; C2-10 alkenyl
C(0)NR4R5; (CR 8 Rg)qC(0)NR4R5; (CR 8 R 8 )q C(O)NR4Rl0; S(0)3R8;
(CR 8 R 8 )qC(0)Ri 1; C 2 -10 alkenylC(0)R 1 1 ; (CR 8 R 8 )qC(0)ORi 1;
C 2 -ioalkenylC(0)ORi 1; (CR 8 R 8 )qOCCO) Rn; (CRgR 8 )qNR4C(0)Rn;
(CR 8 R 8 )q NHS(0) 2 R b ; (CR 8 R 8 )q S(0) 2 NR 4 R 5 ; (CRsR^qCCNR^NR^;
(CR 8 R 8 )q NR4C(NR5)Ri 1; or two Y moieties together may form 0-(CH 2 )sO- or a
5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,
heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally
substituted;

q is 0 or an integer having a value of 1 to 10;

n is an integer having a value of 1 to 3;

m is an integer having a value of 1 to 3;

R 8 is hydrogen or C 1.4 alkyl;

RlO is Ci-10 alkyl C(0)2R8;

Rl 1 is hydrogen, optionally substituted Ci -4 alkyl, optionally substituted aryl,

optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally
substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicC i-4alkyl;

- 134-

WO 97/29743

PCT/US96/13632

Rl2 is hydrogen, Ci-10 alkyl, optionally substituted aryl or optionally substituted
arylalkyl;

Rl3 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl,

heterocyclic, or heterocyclicCi-4alkyl;
or a pharmaceutically acceptably salt thereof.

21 . The compound according to Claim 20 wherein Ri is substituted in the 3-
position, the 4- position or di substituted in the 3,4- position by an electron withdrawing
moiety.

22. The compound according to Claim 20 or 21 wherein Y is mono- substituted in
the 2'-position or 3'- position, or is disubstituted in the 2'- or 3'- position of a
monocyclic ring.

23. The compound according to Claim 20 or 2 1 wherein n amd m are each equal to
1 or more.

24. The compound according to Claim 20 which is
N-(4-Nitro 2-(phenylsulfonylamino)phenyl)-N'-phenyl urea
N-[(2-Phenylsulfamido) 4-cyanophenyl]- N'-(2-bromo phenyl) urea

N-(2-( Amino sulfonamido phenyl) phenyl) N'-(2-bromo phenyl) urea N-(2-( Amino
sulfonyl styryl) phenyl) N'-(2-bromo phenyl) urea 2- [(3,4 Di-
methoxyphenylsulfonyl)amino] phenyl) N'-(2-bromo phenyl) urea N-(2-[(4-
AcetamidophenylsulfonyDamino] phenyl) N'-(2-bromo phenyl) urea N-(2-( Amino
sulfonyl (2-thiophene) phenyl) N'-(2-bromo phenyl) urea N-(2-( Amino sulfonyl (3-
tolyl) phenyl) N'-(2-bromo phenyl) urea N-(2-( Amino sulfonyl (8-quinolinyl)) phenyl)
N'-(2-bromo phenyl) urea N-(2-(Amino sulfonyl benzyl) phenyl) N'-(2-bromo phenyl)
urea

N-[2-[[[2-(Trifluoromethyl)phenyl]sulfonyl]amino]phenyl]-N*-(2-bromophenyl)urea
N-(2-Bromophenyl)-N'-[2-dimethylaminosulfonylamino]phenyl]urea N-[2-
(Phenethylsulfonylamino)phenyl]-N'-(2-bromophenyl)urea N-[2-t(2-Acetamido-4-
methylthiazol-5-yl)sulfonylamino]phenyl]-N'-(2-bromophenyl)ureaN-[2-[(2,3-
Dichlorothien-5-yl)]sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(3,5-Bistrifluoromethylphenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[(2-Benzyl)sulfonylamino]-(5-trifluoromethyl)phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(3-Nitrophenyl)sulfonylamino]phenyl]-N'-(2-bromophenyl)urea

- 135 -

WO 97/29743

PCT/US96/13632

N-[2-[2-(4-Phenoxyphenyl)sulfonylamino]phenyl]-N"-(2-bromophenyl)urea
N-[[2-(lS)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[[2-(lR)-10-Camphorsulfonylamino]phenyl]-N'-(2-bromophenyl)urea
N-[2-[2-(2-Nitro-(4-trifluoromethyl)phenyl)sulfonylamino]phenyl-N'-(2-

5 bromophenyl)urea

N-[2-(2-Amino-(4-trifluoromethyl) phenyl) sulfonylamino] phenyl]- N'-(2-

bromophenyl)urea ; or N-[2-(aminosulfonyl phenyl) 3-amino phenyl] N'-(2-
bromo phenyl) urea.

10 25. A pharmaceutical composition comprising a compound according to any of
Claims 20 to 24 and a pharmaceutically acceptable carrier or diluent.

26. A compound of the formula:

X ir H

15

wherein

X is oxygen or sulfur;
Xi is oxygen or sulfur;

Ri is independently selected from hydrogen; halogen; nitro; cyano; Ci-io alkyl;
20 halosubstituted Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted

Ci-ioalkoxy; azide; S(0) t R4; (CR 8 R 8 )q S(0)tR4; hydroxy; hydroxy substituted

Ci-4alkyl; aryl; aryl C 1-4 alkyl; aryl C2-10 alkenyl; aryloxy; aryl Ci-4 alkyloxy;

heteroaryl; heteroarylalkyl; heteroaryl C2-10 alkenyl; heteroaryl Ci-4 alkyloxy;

heterocyclic, heterocyclic Ci-4alkyl; heterocyclicCi-4alkyloxy; heterocyclicC2-10
25 alkenyl; (CR 8 R 8 )q NR4R5; (CR 8 R 8 )q C(0)NR4Rs; C2-10 alkenyl C(0)NR4R5;

(CR 8 R 8 )q C(O)NR4Rl0; S(0)3R8; (CR 8 R 8 )q C(0)Rl 1; C2-10 alkenyl C(0)Ri i;

C2-10 alkenyl C(0)ORn; (CR 8 R 8 )q C(0)ORi 1; (CR 8 R 8 )q OC(0)Rn ;

(CR 8 R 8 )qNR4C(0)Rl l; (CR 8 R 8 )q C(NR4)NR4R 5 ; (CR 8 R 8 )q NR4C(NR 5 )Ri 1,

(CR 8 R 8 )q NHS(0) 2 Ri3; (CR 8 R 8 )q S(0) 2 NR 4 R 5 , or two Rl moieties together may
30 form 0-(CH2)sO- or a 5 to 6 membered unsaturated ring, and wherein the alkyl, aryl,

arylalkyl, heteroaryl, heterocyclic moities may be optionally substituted;
t is 0, or an integer having a value of 1 or 2;
s is an integer having a value of 1 to 3;

136

SUBSTITUTE SHEET (RULE 26)

PCT/US96/13632

WO 97/29743

R4 and R5 are independently hydrogen, optionally substituted C 1-4 alkyl, optionally
substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted
heteroaryl, optionally substituted heteroaryl C\-4 alkyl, heterocyclic, heterocyclic
Ci-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form
5 a 5 to 7 member ring which may optionally comprise an additional heteroatom

selected from O/N/S;

Y is hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Ci-10 alkyl; C2-10
alkenyl; Ci- 10 alkoxy; halosubstituted Ci- 10 alkoxy; azide; (CR 8 R8)qS(0) t R4,
(CR 8 R 8 )qOR4; hydroxy; hydroxy substituted Ci-4alkyl; aryl; aryl C1-4 alkyl;
10 aryloxy; arylCi-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl; heteroarylalkyl;

heteroaryl Ci-4 alkyloxy; heteroaryl C2-10 alkenyl; heterocyclic, heterocyclic
Ci-4alkyl; heterocyclicC2-10 alkenyl; (CR 8 R 8 )qNR4R5; C2-10 alkenyl
C(0)NR4R5; (CR 8 R 8 )qC(0)NR4R5; (CR 8 R 8 )q C(O)NR4Rl0; S(0)3R8;
(CR 8 R 8 )qC(0)Rn; C2-10alkenylC(O)Rli; (CR 8 R 8 )qQO)ORl 1;
15 C2-10alkenylC(O)ORn; (CR 8 R 8 )qOC(0) Rn; (CR 8 R 8 )qNR4C(0)Rn;

(CR 8 R 8 )q NHS(0) 2 R b ; (CRgR 8 )q S(0) 2 NR4R5. (CR 8 R 8 )qC(NR4)NR4R 5 ;
(CR 8 R 8 )q NR4C(NR5)Ru ; or two Y moieties together may form 0-(CH2) S 0- or a
5 to 6 membered unsaturated ring; and wherein the alkyl, aryl, arylalkyl, heteroaryl,
heteroaryl alkyl, heterocyclic, heterocyclicalkyl groups may be optionally
20 substituted;

q is 0 or an integer having a value of 1 to 10;
n is an integer having a value of 1 to 3 ;
m is an integer having a value of 1 to 3;

R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together
25 with the nitrogen to which they are attached form a 5 to 7 member ring which ring

may optionally contain an additional heteroatom which heteroatom is selected from
oxygen, nitrogen or sulfur;
R 8 is hydrogen or Ci-4 alkyl;
RlO is Ci-10 alkyl C(0)2R8;
30 R 1 1 is hydrogen, optionally substituted C 1 -4 alkyl, optionally substituted aryl,

optionally substituted aryl Ci-4alkyl. optionally substituted heteroaryl, optionally
substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally
substituted heterocyclicCi-4alkyl;
Rl2 is hydrogen, Ci-10 alkyl, optionally substituted aryl or optionally substituted

35 arylalkyl;

R13 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl,
heterocyclic, or heterocyclicCi-4alkyl;

- 137 -

WO 97/29743 PCT/US96/13632

Rb is NR5R7, alkyl, aryl, aryl C1.4 alkyl, aryl C2.4 alkenyl, heteroaryl, heteroaryl
Ci_4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C1.4 alkyl.
heterocyclic C2.4 alkenyl, or camphor, all of which groups may be optionally
substituted; provided that
5 when n =1 than Y is substituted in the 2- or 3- position;

when n =2 than Y is di-substituted in the 2'- 3'- position, the 2'-5'- position, the

2'-6' position, the 3'-5' or the 3'-6' position;
when n = 3 than Y is trisubstituted in the 2'-3'-5' or the 2'-3'-6'- positions;
further provided that

10 when Xi is O, m=2, Ri is 2-t-butyl, 4-methyl, and n=3 than Y is not 2'-OH,3'-t-

butyl, 5'-methyl;

when Xi is O, m=l, Ri is 4-methyl, and n=2 than Y is not 2'-OH, 5'-methyl;
when Xi is O, m=l, Ri is hydrogen, and n=2 than Y is not 2'-6'-diethyl;
when Xi is O, m=l, Ri is 6-OH, and n=2 than Y is not 2'-5'-methyl;
15 when X 1 is S, m=l, Rj is 4-ethyl, and n=l than Y is not 2-methoxy;

or a pharmaceutically acceptably salt thereof.

27. The compound according to Claim 26 wherein Ri is substituted in the 3-
position, the 4- position or di-substituted in the 3,4- position by an electron withdrawing

20 moiety.

28. The compound according to Claim 26 or 27 wherein Y is mono-substituted in
the 2 -position or 3 - position, or is disubstituted in the 2' or 3' position of a monocyclic
ring.

25

29. The compound according to Claim 26 or 27 wherein n amd m are each equal to
1 or more.

30. A pharmaceutical composition comprising a compound according to any of
30 Claims 26 to 29 and a pharmaceutically acceptable carrier or diluent.

31. A process for producing a cyano phenol derivative of the formula:

OH

- 138-

WO 97/29743 PCT/US96/13632

w

herein Rl is as defined for Formula (I) above, which method comprises

a) reacting a compound of the formula:

OH

-x

R i wherein X is halogen

with copper (I) cyanide, dimethylformamide, triethylamine and a catalytic amount of
5 dimethylamino pyridine.

32. The process according to Claim 3 1 wherein the temperature is about 60 to about
80° C, and X is bromine.

10

- 139-

INTERNATIONAL SEARCH REPORT

International application No.
PCT/US96/ 13632

A. CLASSIFICATION OF SUBJECT MATTER

IPC(6) :A61K 31/17

US CL : 514/585, 596, 597,598
According to International Patent Clarification (IPC) or to both national classification and IPC

B. FIELDS SEARCHED

Minimum documentation aearched (clarification lyatem followed by classification symbols)
U.S. : 514/585,596,597,598

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
None

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
Please See Extra Sheet.

DOCUMENTS CONSIDERED TO BE RELEVANT

Category*

Citation of document, with indication, where appropriate, of the relevant passages

Relevant to claim No.

US, A, 5,384,319 (FERRINI) 24 January 1995, see claims 1-
11.

US, A, 5,312.831 (AYRAL-KALOUSTIAN ET AL) 17 May
1994, see claims 1 and 25.

US,A, 4,048,333 (GALABOV ET AL) 13 September 1977,
entire document.

1-9.1 1-16,20-
24,28,29,31,32

1-9,11-16,2 0-
24,28,29,31,32

1 -9,20-
24,28,29

[ | Further documents are listed in the continuation of Box C. |Q See patent family annex.

* SnacWcttecamnf ctad docvMBB- T iMcr document publkhed after the mtonwnoaadfuiaa. dale or priority

dale arai not in conflict with the appbeahon but cited to underacaed the
•A* doaimtaatdefmil«,the e,eneral «ak of the art which ia net oonaiderad principle or theory underlying die invention
to be of pellicular relevance

"X" docaencot of particular relevance; the claimed invention cannot be
"E* earlier rinnarwul publiahed oo or after the international filmf dale conaaieroi novel or cannot be cooaklered to involve an inventive alzp

•L- ck>c«r-aal which nay throw doubt! on priority claimC) or whicn ia when the document ■ taken alone

riled to ■tehhuh the gMMioa dete of aooaber ritabo. or other . y . 1lrr ,-* of eautjeuhu- — ; 1 i ~ ' be

■»•*"* '">" V*» njectflea) oomeieted to involve en brventlve etep when the document ia

■O' document rtfmwie to an oral diac 1 — exnabitton ~ other cemnmed wilb one or mora . other eucfc doetnaunan. aucfc continuation

gpgg,, beaa*. obvioue to ■ peraoo akilled in the art

■P* . TWlMhh— ' r^*— *" "**' Tt—T"* 1 fil '"t ***** Out later dim document " f "»" — tim p.-*"* fcmity

Date of the actual completion of the international search
09 DECEMBER 1996

Date of mailing of the international search report

2 7 DEC 1996

Name and mailing address of the ISA/US
Commiaaioeier of Patent! and Trademark*
BoxPCT

Washington, D C. 20231
Facsimile No. (703) 305-3230

Authorized ofCcery^^ yj^ ^\^\£M^

DWAYNE C JONES
Telephone No. (703) 308-1235

Form PCT/ISA/210 (second sheetXJuly 1992)*

INTERNATIONAL SEARCH REPORT

International application No.
PCT/US96/13632

Box I Observations where certain claims were foand unsearchable (Continuation of item 1 of first sheet)
Thk international report has not been established in respect of certain claims under Article 17(2Xa) for the following

□

Claims Nos.:

because they relate to subject matter not required to be searched by this Authority, namely:

□

Claims Nos.:

because they relate to parts of the international application that do not comply with the prescribed requirement! to such
an extent that no meaningful international search can be carried out, ipecifically:

3. [x] Claims Nos.: 10, 27, 30

because they arc dependent claimi and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Boat II Obsecrations where unity of uiTentioa is lacking (Continuation of hem 2 of Tint sheet)
This International Searching Authority found multiple inventions in this international application, as follows:
Please See Extra Sheet.

! ' CD *? ^ "qui«d additional search fees were timely paid by the applicant. thU international .earch report covers all searchable

claims

2. Q As all searchable claims could be searched without effort justifying an additional fee. this Authority did not invite payment
of any additional fee.

3 D A, i on |y *° me ofthc sdditional search fees were timely paid by the applicant, this international search report covers

only those claims for which fees were paid, specifically claims Nos.:

4 03 N ° rcquircd wMtoonal search fees were timely paid by the applicant. Consequently, this international search report is
reatneted to the invention first mentioned in the claims; it is covered by claims Nos •
1-9,11-16,20-24,28,29,31,32

Remark on Protest Q The additional search fees were accompanied by the applicant's protest

□

No protest accompanied the payment of additional search fees.

Form PCT/1SA/210 (continuation of first sheet(l))(July 1992)*

INTERNATIONAL SEARCH REPORT

International application No.
PCT/US96/13632

B. FIELDS SEARCHED

Electronic data bases consulted (Name of data bate and where practicable terms used):

STN: the structure of formula I. BIOSIS: the structure of formula I, chemolrin? or interleukin? or il-8, psoriss?,
dennatit?, asthma?, thrombo?, alzheuner?, stroke, crohn? disease?, nephrit?, glomerul?, pulmonary diseas?, arthrit?,
inflammatory bowel? CLAIMS: cytokdnc##, Lnterieukin*#, antiinflammatroy (3a)agcnt/C , chemotaxia, urea or thiourea
functional groups.

BOX B. OBSERVATIONS WHERE UNITY OF INVENTION WAS LACKING
This ISA found multiple inventions as follows:

This application contains the following inventions or groups of inventions which are not so linked as to form a single
inventive concept under PCT Rule 13.1. In order for all inventions to be searched, the appropriate additional search
fees must be paid.

I. Clajms 1-16, 20-32, drawn to a first compound, pharmaceutical compositions, a method of use, and a method
of production.

II. Claims 17-18, drawn to second compound, and pharmaceutical compositions.
CI. Claim 19, drawn to a method of using the second compound.

The inventions listed aa Groups I-m do not relate to a single inventive concept under PCT Rule 13.1 because, under
PCT Rule 13.2, they lack the same or corresponding special technical features for the following reasons: The two
groups possess two different core rookie*. Those compounds of Group I have a urea attached between two phenyl
groups; while Group 0 compounds hava a urea attached between a carbocyclic ring and a heteroaryl group. These two
core rookies do not have a common technical feature and therefore lack unity of invention. Pursuant to 37 CFR
1.475(d) the second method of use (of the second product) is grouped separately from the second product.

Form PCT/ISA/210 (extra sheet)(July 1992)*